3-aryl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors

ABSTRACT

The present disclosure relates to inhibitors of zinc-dependent histone deacetylases (HDACs) useful in the treatment of diseases or disorders associated with an HDAC, e.g., HDAC6, having a Formula I: 
                         
where R, L, X 1 , X 2 , X 3 , X 4 , Y 1 , Y 2 , Y 3 , and Y 4  are described herein.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. Non-Provisional applicationSer. No. 15/013,816, filed Feb. 2, 2016, which claims the benefit ofpriority of U.S. Provisional Application No. 62/110,716, filed Feb. 2,2015 and U.S. Provisional Application No. 62/205,438, filed Aug. 14,2015, each of which is incorporated herein by reference.

FIELD OF THE DISCLOSURE

The present disclosure relates to inhibitors of zinc-dependent histonedeacetylases (HDACs) useful in the treatment of diseases or disordersassociated with HDACs including cell proliferation diseases (e.g.,cancer), neurological and inflammatory diseases. Specifically, thisdisclosure is concerned with compounds and compositions inhibitingHDACs, methods of treating diseases associated with HDACs, and methodsof synthesizing these compounds.

BACKGROUND OF THE DISCLOSURE

Many members of the HDAC family require zinc (Zn) to function properly.For instance, the isozyme histone deacetylase 6 (HDAC6) is azinc-dependent histone deacetylase that possesses histone deacetylaseactivity. Other family members include HDACs 1-5 and 7-11. (De Ruijteret al, Biochem. J. 2003. 370; 737-749).

HDAC6 is known to deacetylate and associate with α-tubulin, cortactin,heat shock protein 90, ß-catenin, glucose-regulated protein 78 kDa,myosin heavy chain 9, heat shock cognate protein 70, and dnaJ homologsubfamily A member 1 (reviewed in Li et al, FEBS J. 2013, 280: 775-93;Zhang et al, Protein Cell. 2015, 6(1): 42-54). Diseases in which HDAC6inhibition could have a potential benefit include cancer (reviewed inAldana-Masangkay et al, J. Biomed. Biotechnol. 2011, 875824),specifically: multiple myeloma (Hideshima et al, Proc. Natl. Acad. Sci.USA 2005, 102(24):8567-8572); lung cancer (Kamemura et al, Biochem.Biophys. Res. Commun. 2008, 374(1):84-89); ovarian cancer (Bazzaro etal, Clin. Cancer Res. 2008, 14(22):7340-7347); breast cancer (Lee et al,Cancer Res. 2008, 68(18):7561-7569; Park et al, Oncol. Rep. 2011, 25:1677-81; Rey et al, Eur. J. Cell Biol. 2011, 90: 128-35); prostatecancer (Seidel et al, Biochem Pharmacol. 2015 (15)00714-5); pancreaticcancer (Nawrocki et al, Cancer Res. 2006, 66(7):3773-3781); renal cancer(Cha et al, Clin. Cancer Res. 2009, 15(3): 840-850); hepatocellularcancer (Ding et al, FEBS Lett. 2013, 587:880-6; Kanno et al, Oncol. Rep.2012, 28: 867-73); lymphomas (Ding et al, Cancer Cell Int. 2014, 14:139;Amengual et al, Clin Cancer Res. 2015, 21(20):4663-75); and leukemiassuch as acute myeloid leukemia (AML) (Fiskus et al, Blood 2008,112(7):2896-2905) and acute lymphoblastic leukemia (ALL)(Rodriguez-Gonzalez et al, Blood 2008, 112(11): Abstract 1923)).

Inhibition of HDAC6 may also have a role in cardiovascular disease,including pressure overload, chronic ischemia, andinfarction-reperfusion injury (Tannous et al, Circulation 2008,117(24):3070-3078); bacterial infection, including those caused byuropathogenic Escherichia coli (Dhakal and Mulve, J. Biol. Chem. 2008,284(1):446-454); neurological diseases caused by accumulation ofintracellular protein aggregates such as Alzheimer's, Parkinson's andHuntington's disease (reviewed in Simoes-Pires et al, Mol. Neurodegener.2013, 8: 7) or central nervous system trauma caused by tissue injury,oxidative-stress induced neuronal or axomal degeneration (Rivieccio etal, Proc. Natl. Acad. Sci. USA 2009, 106(46):19599-195604); andinflammation and autoimmune diseases through enhanced T cell-mediatedimmune tolerance at least in part through effects on regulatory T cells,including rheumatoid arthritis, psoriasis, spondylitis arthritis,psoriatic arthritis, multiple sclerosis, lupus, colitis and graft versushost disease (reviewed in Wang et al, Nat. Rev. Drug Disc. 20098(12):969-981; Vishwakarma et al, Int. Immunopharmacol. 2013, 16:72-8;Kalin et al, J. Med Chem. 2012, 55:639-51); and fibrotic disease,including kidney fibrosis (Choi et al, Vascul. Pharmacol. 201572:130-140).

Four HDAC inhibitors are currently approved for the treatment of somecancers. These are suberanilohydroxamic acid (Vorinostat; Zolinza®) forthe treatment of cutaneous T cell lymphoma and multiple myeloma;Romidepsin (FK228; FR901228; Istodax®) for the treatment of peripheral Tcell lymphoma; Panobinostat (LBH-589; Farydak®) for the treatment ofmultiple myeloma; and belinostat (PXD101; Beleodaq®) for the treatmentof peripheral T cell lymphoma. However, these drugs are of limitedeffectiveness and can give rise to unwanted side effects. Thus there isa need for drugs with an improved safety-efficacy profile.

Given the complex function of HDAC6 and their potential utility in thetreatment of proliferative diseases, neurological diseases, andinflammatory diseases, there is a need for HDAC inhibitors (e.g., HDAC6inhibitors) with good therapeutic properties.

SUMMARY OF THE DISCLOSURE

One aspect of the disclosure relates to compounds of Formula I:

and pharmaceutically acceptable salts, prodrugs, solvates, hydrates,tautomers and isomers thereof,

wherein:

X¹ is independently CR¹R², NR³, O, or C═O;

X² and X⁴ are each independently CR¹R², C═O, S(O) or SO₂;

X³ is CR^(1′)R^(2′); wherein X⁴, X², and X¹ are not all simultaneouslyCR¹R²;

Y¹ and Y⁴ are not bonded to —C(O)NHOH and are each independently N orCR¹;

Y² and Y³ are each independently N or CR¹ when not bonded to —C(O)NHOHand Y² and Y³, are C when bonded to —C(O)NHOH;

L is —C(O)—, —C(O)(CR¹R²)_(m)—, or —C(O)(CR¹R²)_(m)O—, wherein L isbound to the ring nitrogen through the carbonyl group;

R is independently, and at each occurrence, —H, —C₁-C₆ alkyl, —C₂-C₆alkenyl, —C₄-C₈ cycloalkenyl, —C₂-C₆ alkynyl, —C₃-C₈ cycloalkyl, —C₅-C₁₂spirocycle, heterocyclyl, spiroheterocyclyl, aryl, or heteroarylcontaining 1 to 5 heteroatoms selected from the group consisting of N,S, P, and O, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl,cycloalkyl, spirocycle, heterocyclyl, spiroheterocyclyl, aryl, orheteroaryl is optionally substituted with one or more —OH, halogen, oxo,—NO₂, —CN, —R¹, —R², —OR³, —NHR³, —NR³R⁴, —S(O)₂NR³R⁴, —S(O)₂R¹,—C(O)R¹, —CO₂R¹, —NR³S(O)₂R¹, —S(O)R¹, —S(O)NR³R⁴, —NR³S(O)R¹,heterocycle, aryl, or heteroaryl containing 1 to 5 heteroatoms selectedfrom the group consisting of N, S, P, and O, with the proviso that R isnot bound to L via a nitrogen atom;

each R¹ and R² are independently, at each occurrence, —H, —R³, —R⁴,—C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₄-C₈ cycloalkenyl, —C₂-C₆ alkynyl,—C₃-C₈ cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1 to 5heteroatoms selected from the group consisting of N, S, P, and O, —OH,halogen, —NO₂, —CN, —NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆alkyl)₂, —N(C₁-C₆ alkyl)S(O)₂R⁵, —S(O)₂C₁-C₆ alkyl, —(C₁-C₆alkyl)S(O)₂R⁵, —C(O)C₁-C₆ alkyl, —CO₂C₁-C₆ alkyl, —N(C₁-C₆alkyl)S(O)₂C₁-C₆ alkyl, or —(CHR⁵)_(n)NR³R⁴, wherein each alkyl,alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, orheteroaryl is optionally substituted with one or more substituentsselected from —OH, halogen, —NO₂, oxo, —CN, —R⁵, —OR³, —NHR³, —NR³R⁴,—S(O)₂N(R³)₂, —S(O)₂R⁵, —C(O)R⁵, —CO₂R⁵, —NR³S(O)₂R⁵, —S(O)R⁵,—S(O)NR³R⁴, —NR³S(O)R⁵, heterocycle, aryl, and heteroaryl containing 1to 5 heteroatoms selected from the group consisting of N, S, P, and O;

or R¹ and R² can combine with the atom to which they are both attachedto form a spirocycle, spiroheterocycle, or a spirocycloalkenyl;

or R¹ and R², when on adjacent atoms, can combine to form a heterocycle,cycloalkyl, cycloalkenyl, aryl, or heteroaryl containing 1 to 5heteroatoms selected from the group consisting of N, S, P, and O;

or R¹ and R², when on non-adjacent atoms, can combine to form a bridgingcycloalkyl, cycloalkenyl, or heterocycloalkyl;

each R^(1′) and R^(2′) are each independently H, aryl, or heteroarylcontaining 1 to 5 heteroatoms selected from the group consisting of N,S, P, and O, wherein each aryl or heteroaryl is optionally substitutedwith one or more substituents selected from —OH, halogen, —NO₂, oxo,—CN, —R³, —R⁵, —OR³, —NHR³, —NR³R⁴, —S(O)₂N(R³)₂, —S(O)₂R⁵, —C(O)R⁵,—CO₂R⁵, —NR³S(O)₂R⁵, —S(O)R⁵, —S(O)NR³R⁴, —NR³S(O)R⁵, heterocycle, aryl,and heteroaryl containing 1 to 5 heteroatoms selected from the groupconsisting of N, S, P, and O, wherein at least one of R^(1′) or R^(2′)is not H;

R³ and R⁴ are independently, at each occurrence, —H, —C₁-C₆ alkyl,—C₂-C₆ alkenyl, —C₄-C₈ cycloalkenyl, —C₂-C₆ alkynyl, —C₃-C₈ cycloalkyl,heterocyclyl, aryl, heteroaryl containing 1 to 5 heteroatoms selectedfrom the group consisting of N, S, P, and O, —S(O)₂N(C₁-C₆ alkyl)₂,—S(O)₂C₁-C₆ alkyl, —(C₁-C₆ alkyl)S(O)₂R⁵, —C(O)C₁-C₆ alkyl, —CO₂C₁-C₆alkyl, or —(CHR⁵)—N(C₁-C₆ alkyl)₂, wherein each alkyl, alkenyl,cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl isoptionally substituted with one or more substituents selected from —OH,halogen, —NO₂, oxo, —CN, —R⁵, —O(C₁-C₆)alkyl, —NHC₁-C₆ alkyl, N(C₁-C₆alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)₂NH(C₁-C₆ alkyl), —C(O)C₁-C₆ alkyl,—CO₂C₁-C₆ alkyl, —N(C₁-C₆ alkyl)S(O)₂C₁-C₆ alkyl, —S(O)R⁵, —S(O)N(C₁-C₆alkyl)₂, —N(C₁-C₆ alkyl)S(O)R⁵, heterocycle, aryl, and heteroarylcontaining 1 to 5 heteroatoms selected from the group consisting of N,S, P, and O;

R⁵ is independently, at each occurrence, —H, —C₁-C₆ alkyl, —C₂-C₆alkenyl, —C₄-C₈ cycloalkenyl, —C₂-C₆ alkynyl, —C₃-C₈ cycloalkyl,heterocyclyl, aryl, heteroaryl containing 1 to 5 heteroatoms selectedfrom the group consisting of N, S, P, and O, —OH, halogen, —NO₂, —CN,—NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂, —S(O)₂NH(C₁-C₆ alkyl), —S(O)₂N(C₁-C₆alkyl)₂, —S(O)₂C₁-C₆ alkyl, —C(O)C₁-C₆ alkyl, —CO₂C₁-C₆ alkyl, —N(C₁-C₆alkyl)SO₂C₁-C₆ alkyl, —S(O)(C₁-C₆ alkyl), —S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)(C₁-C₆ alkyl) or —(CH₂)_(n)N(C₁-C₆ alkyl)₂; and

each n is independently and at each occurrence an integer from 0 to 6;

each m is independently and at each occurrence an integer from 1 to 6;and

provided that when X² and X⁴ are both C═O, X¹ is not NR³.

Another aspect of the disclosure relates to a method of treating adisease or disorder associated with HDAC6 modulation in a subject inneed thereof, comprising administering to the subject an effectiveamount of a compound of Formula I, or a pharmaceutically acceptablesalt, prodrug, solvate, hydrate, tautomer, or isomer thereof.

Another aspect of the disclosure is directed to a method of inhibitingHDAC6. The method involves administering to a patient in need thereof aneffective amount of a compound of Formula I, or a pharmaceuticallyacceptable salt, prodrug, solvate, hydrate, tautomer, or isomer thereof.

Another aspect of the disclosure relates to a compound of Formula I, ora pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer,or isomer thereof, for use in treating or preventing a diseaseassociated with HDAC6 modulation.

Another aspect of the disclosure relates to the use of a compound ofFormula I, or a pharmaceutically acceptable salt, prodrug, solvate,hydrate, tautomer, or isomer thereof, in the manufacture of a medicamentfor treating or preventing a disease associated with HDAC6 modulation.

Another aspect of the disclosure is directed to pharmaceuticalcompositions comprising a compound of Formula I, or a pharmaceuticallyacceptable salt, prodrug, solvate, hydrate, tautomer, or isomer thereof,and a pharmaceutically acceptable carrier. The pharmaceuticallyacceptable carrier can further include an excipient, diluent, orsurfactant. The pharmaceutical composition can be effective for treatinga disease or disorder associated with HDAC6 modulation in a subject inneed thereof. The pharmaceutical compositions can comprise the compoundsof the present disclosure for use in treating diseases described herein.The compositions can contain at least one compound of the disclosure anda pharmaceutically acceptable carrier. The disclosure also provides theuse of the compounds described herein in the manufacture of a medicamentfor the treatment of a disease associated with HDACs.

The present disclosure also provides methods for the treatment of humandiseases or disorders including, without limitation, oncological,neurological, inflammatory, autoimmune, infectious, metabolic,hematologic, or cardiovascular diseases or disorders.

The present disclosure also provides compounds that are useful ininhibiting of zinc-dependent HDAC enzymes, and in particular HDAC6.These compounds can also be useful in the treatment of diseasesincluding cancer.

The present disclosure further provides compounds that can inhibit anHDAC, e.g., HDAC6. In some embodiments, the efficacy-safety profile ofthe compounds of the current disclosure can be improved relative toother known HDAC (e.g., HDAC6) inhibitors. Additionally, the presenttechnology also has the advantage of being able to be used for a numberof different types of diseases, including cancer and non-cancerindications. Additional features and advantages of the presenttechnology will be apparent to one of skill in the art upon reading theDetailed Description of the Disclosure, below.

DETAILED DESCRIPTION OF THE DISCLOSURE

HDAC6 is a zinc-dependent histone deacetylase that has two catalyticdomains. HDAC6 can interact with and deacetylate non-histone proteins,including HSP90 and α-tubulin. Acetylation of HSP90 is associated withloss of function of HSP90. HDAC6 is also implicated in the degradationof misfolded proteins as part of the aggresome. Accordingly, inhibitionof an HDAC, e.g., HDAC6 can have downstream effects that can play a rolein the development of certain diseases such as cancer. The presentdisclosure provides inhibitors of an HDAC, e.g., HDAC6 and methods forusing the same to treat disease.

In a first aspect of the disclosure, compounds of the Formula I aredescribed:

and pharmaceutically acceptable salts, prodrugs, solvates, hydrates,tautomers, and isomers thereof, wherein R, L, X¹, X², X³, X⁴, Y¹, Y²,Y³, and Y⁴ are as described herein above.

The details of the disclosure are set forth in the accompanyingdescription below. Although methods and materials similar or equivalentto those described herein can be used in the practice or testing of thepresent disclosure, illustrative methods and materials are nowdescribed. Other features, objects, and advantages of the disclosurewill be apparent from the description and from the claims. In thespecification and the appended claims, the singular forms also includethe plural unless the context clearly dictates otherwise. Unless definedotherwise, all technical and scientific terms used herein have the samemeaning as commonly understood by one of ordinary skill in the art towhich this disclosure belongs. All patents and publications cited inthis specification are incorporated herein by reference in theirentireties.

Definitions

The articles “a” and “an” are used in this disclosure to refer to one ormore than one (e.g., to at least one) of the grammatical object of thearticle. By way of example, “an element” means one element or more thanone element.

The term “and/or” is used in this disclosure to mean either “and” or“or” unless indicated otherwise.

The term “optionally substituted” is understood to mean that a givenchemical moiety (e.g., an alkyl group) can (but is not required to) bebonded other substituents (e.g., heteroatoms). For instance, an alkylgroup that is optionally substituted can be a fully saturated alkylchain (e.g., a pure hydrocarbon). Alternatively, the same optionallysubstituted alkyl group can have substituents different from hydrogen.For instance, it can, at any point along the chain be bounded to ahalogen atom, a hydroxyl group, or any other substituent describedherein. Thus the term “optionally substituted” means that a givenchemical moiety has the potential to contain other functional groups,but does not necessarily have any further functional groups.

The term “aryl” refers to cyclic, aromatic hydrocarbon groups that have1 to 2 aromatic rings, including monocyclic or bicyclic groups such asphenyl, biphenyl or naphthyl. Where containing two aromatic rings(bicyclic, etc.), the aromatic rings of the aryl group may be joined ata single point (e.g., biphenyl), or fused (e.g., naphthyl). The arylgroup may be optionally substituted by one or more substituents, e.g., 1to 5 substituents, at any point of attachment. Exemplary substituentsinclude, but are not limited to, —H, -halogen, —O—C₁-C₆ alkyl, —C₁-C₆alkyl, —OC₂-C₆ alkenyl, —OC₂-C₆ alkynyl, —C₂-C₆ alkenyl, —C₂-C₆ alkynyl,—OH, —OP(O)(OH)₂, —OC(O)C₁-C₆ alkyl, —C(O)C₁-C₆ alkyl, —OC(O)OC₁-C₆alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —S(O)₂—C₁-C₆ alkyl,—S(O)NHC₁-C₆ alkyl, and —S(O)N(C₁-C₆ alkyl)₂. The substituents canthemselves be optionally substituted. Furthermore when containing twofused rings the aryl groups herein defined may have an unsaturated orpartially saturated ring fused with a fully saturated ring. Exemplaryring systems of these aryl groups include indanyl, indenyl,tetrahydronaphthalenyl, and tetrahydrobenzoannulenyl.

Unless otherwise specifically defined, “heteroaryl” means a monovalentmonocyclic aromatic radical of 5 to 24 ring atoms or a polycyclicaromatic radical, containing one or more ring heteroatoms selected fromN, S, P, and O, the remaining ring atoms being C. Heteroaryl as hereindefined also means a bicyclic heteroaromatic group wherein theheteroatom is selected from N, S, P, and O. The aromatic radical isoptionally substituted independently with one or more substituentsdescribed herein. Examples include, but are not limited to, furyl,thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl,isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl,quinolyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole,benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl,imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl,indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl,pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl,thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl,indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl,benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl,dihydrobenzothiazine, dihydrobenzoxanyl, quinolinyl, isoquinolinyl,1,6-naphthyridinyl, benzo[de]isoquinolinyl,pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl,tetrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl,pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl,pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl,pyrrolo[1,2-a]pyrimidinyl, tetrahydro pyrrolo[1,2-a]pyrimidinyl,3,4-dihydro-2H-1λ²-pyrrolo[2,1-b]pyrimidine, dibenzo[b,d] thiophene,pyridin-2-one, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl,1H-pyrido[3,4-b][1,4] thiazinyl, benzooxazolyl, benzoisoxazolyl,furo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthyridinyl,furo[3,2-b]pyridine, [1,2,4]triazolo[1,5-a]pyridinyl,benzo[1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl,[1,2,4]triazolo[4,3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl,benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one,3,4-dihydro-2H-pyrazolo[1,5-b][1,2]oxazinyl,4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4-d]thiazolyl,imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, 3H-indolyl,and derivatives thereof. Furthermore when containing two fused rings theheteroaryl groups herein defined may have an unsaturated or partiallysaturated ring fused with a fully saturated ring. Exemplary ring systemsof these heteroaryl groups include indolinyl, indolinonyl,dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl,tetrahydroquinolinyl, dihydrobenzothiazine,3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuran, indolinyl, indolyl,and dihydrobenzoxanyl.

“Alkyl” refers to a straight or branched chain saturated hydrocarbon.C₁-C₆ alkyl groups contain 1 to 6 carbon atoms. Examples of a C₁-C₆alkyl group include, but are not limited to, methyl, ethyl, propyl,butyl, pentyl, isopropyl, isobutyl, sec-butyl and tert-butyl, isopentyland neopentyl.

The term “alkenyl” means an aliphatic hydrocarbon group containing acarbon-carbon double bond and which may be straight or branched havingabout 2 to about 6 carbon atoms in the chain. Alkenyl groups can have 2to about 4 carbon atoms in the chain. Branched means that one or morelower alkyl groups such as methyl, ethyl, or propyl are attached to alinear alkenyl chain. Exemplary alkenyl groups include ethenyl,propenyl, n-butenyl, and i-butenyl. A C₂-C₆ alkenyl group is an alkenylgroup containing between 2 and 6 carbon atoms.

The term “alkynyl” means an aliphatic hydrocarbon group containing acarbon-carbon triple bond and which may be straight or branched havingabout 2 to about 6 carbon atoms in the chain. Alkynyl groups can have 2to about 4 carbon atoms in the chain. Branched means that one or morelower alkyl groups such as methyl, ethyl, or propyl are attached to alinear alkynyl chain. Exemplary alkynyl groups include ethynyl,propynyl, n-butynyl, 2-butynyl, 3-methylbutynyl, and n-pentynyl. A C₂-C₆alkynyl group is an alkynyl group containing between 2 and 6 carbonatoms.

The term “cycloalkyl” means monocyclic or polycyclic saturated carbonrings containing 3-18 carbon atoms. Examples of cycloalkyl groupsinclude, without limitations, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptanyl, cyclooctanyl, norboranyl, norborenyl,bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl. A C₃-C₈ cycloalkyl is acycloalkyl group containing between 3 and 8 carbon atoms. A cycloalkylgroup can be fused (e.g., decalin) or bridged (e.g., norbornane).

The term “cycloalkenyl” means monocyclic, non-aromatic unsaturatedcarbon rings containing 3-18 carbon atoms. Examples of cycloalkenylgroups include, without limitation, cyclopentenyl, cyclohexenyl,cycloheptenyl, cyclooctenyl, and norborenyl. A C₃-C₈ cycloalkenyl is acycloalkenyl group containing between 3 and 8 carbon atoms.

The terms “heterocyclyl” or “heterocycloalkyl” or “heterocycle” refer tomonocyclic or polycyclic 3 to 24-membered rings containing carbon andheteroatoms taken from oxygen, nitrogen, or sulfur and wherein there isnot delocalized π electrons (aromaticity) shared among the ring carbonor heteroatoms. Heterocyclyl rings include, but are not limited to,oxetanyl, azetadinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl,oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl,tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl,thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide,piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, and homotropanyl.A heterocyclyl or heterocycloalkyl ring can also be fused or bridged,e.g., can be a bicyclic ring.

As used herein, the term “halo” or “halogen” means fluoro, chloro,bromo, or iodo.

The term “carbonyl” refers to a functional group composing a carbon atomdouble-bonded to an oxygen atom. It can be abbreviated herein as “oxo”,as C(O), or as C═O.

“Spirocycle” or “spirocyclic” means carbogenic bicyclic ring systemswith both rings connected through a single atom. The ring can bedifferent in size and nature, or identical in size and nature. Examplesinclude spiropentane, spirohexane, spiroheptane, spirooctane,spirononane, or spirodecane. One or both of the rings in a spirocyclecan be fused to another ring carbocyclic, heterocyclic, aromatic, orheteroaromatic ring. One or more of the carbon atoms in the spirocyclecan be substituted with a heteroatom (e.g., O, N, S, or P). A C₃-C₁₂spirocycle is a spirocycle containing between 5 and 12 carbon atoms. Oneor more of the carbon atoms can be substituted with a heteroatom.

The term “spirocyclic heterocycle” or “spiroheterocycle” is understoodto mean a spirocycle wherein at least one of the rings is a heterocycle(e.g., at least one of the rings is furanyl, morpholinyl, orpiperadinyl).

The disclosure also includes pharmaceutical compositions comprising aneffective amount of a disclosed compound and a pharmaceuticallyacceptable carrier. Representative “pharmaceutically acceptable salts”include, e.g., water-soluble and water-insoluble salts, such as theacetate, amsonate (4,4-diaminostilbene-2,2-disulfonate),benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate,bromide, butyrate, calcium, calcium edetate, camsylate, carbonate,chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate,estolate, esylate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine,hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate,lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate,mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate,napsylate, nitrate, N-methylglucamine ammonium salt,3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate(1,1-methene-bis-2-hydroxy-3-naphthoate, einbonate), pantothenate,phosphate/diphosphate, picrate, polygalacturonate, propionate,p-toluenesulfonate, salicylate, stearate, subacetate, succinate,sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate,tosylate, triethiodide, and valerate salts.

The term “stereoisomers” refers to the set of compounds which have thesame number and type of atoms and share the same bond connectivitybetween those atoms, but differ in three dimensional structure. The term“stereoisomer” refers to any member of this set of compounds.

The term “diastereomers” refers to the set of stereoisomers which cannotbe made superimposable by rotation around single bonds. For example,cis- and trans-double bonds, endo- and exo-substitution on bicyclic ringsystems, and compounds containing multiple stereogenic centers withdifferent relative configurations are considered to be diastereomers.The term “diastereomer” refers to any member of this set of compounds.In some examples presented, the synthetic route may produce a singlediastereomer or a mixture of diastereomers. In some cases thesediastereomers were separated and in other cases a wavy bond is used toindicate the structural element where configuration is variable.

The term “enantiomers” refers to a pair of stereoisomers which arenon-superimposable mirror images of one another. The term “enantiomer”refers to a single member of this pair of stereoisomers. The term“racemic” refers to a 1:1 mixture of a pair of enantiomers.

The term “tautomers” refers to a set of compounds that have the samenumber and type of atoms, but differ in bond connectivity and are inequilibrium with one another. A “tautomer” is a single member of thisset of compounds. Typically a single tautomer is drawn but it isunderstood that this single structure is meant to represent all possibletautomers that might exist. Examples include enol-ketone tautomerism.When a ketone is drawn it is understood that both the enol and ketoneforms are part of the disclosure.

An “effective amount” when used in connection with a compound is anamount effective for treating or preventing a disease in a subject asdescribed herein.

The term “carrier”, as used in this disclosure, encompasses carriers,excipients, and diluents and means a material, composition or vehicle,such as a liquid or solid filler, diluent, excipient, solvent orencapsulating material, involved in carrying or transporting apharmaceutical agent from one organ, or portion of the body, to anotherorgan, or portion of the body of a subject.

The term “treating” with regard to a subject, refers to improving atleast one symptom of the subject's disorder. Treating includes curing,improving, or at least partially ameliorating the disorder.

The term “disorder” is used in this disclosure to mean, and is usedinterchangeably with, the terms disease, condition, or illness, unlessotherwise indicated.

The term “administer”, “administering”, or “administration” as used inthis disclosure refers to either directly administering a disclosedcompound or pharmaceutically acceptable salt of the disclosed compoundor a composition to a subject, or administering a prodrug derivative oranalog of the compound or pharmaceutically acceptable salt of thecompound or composition to the subject, which can form an equivalentamount of active compound within the subject's body.

The term “prodrug,” as used in this disclosure, means a compound whichis convertible in vivo by metabolic means (e.g., by hydrolysis) to adisclosed compound. Furthermore, as used herein a prodrug is a drugwhich is inactive in the body, but is transformed in the body typicallyeither during absorption or after absorption from the gastrointestinaltract into the active compound. The conversion of the prodrug into theactive compound in the body may be done chemically or biologically(e.g., using an enzyme).

The term “solvate” refers to a complex of variable stoichiometry formedby a solute and solvent. Such solvents for the purpose of the disclosuremay not interfere with the biological activity of the solute. Examplesof suitable solvents include, but are not limited to, water, MeOH, EtOH,and AcOH. Solvates wherein water is the solvent molecule are typicallyreferred to as hydrates. Hydrates include compositions containingstoichiometric amounts of water, as well as compositions containingvariable amounts of water.

The term “isomer” refers to compounds that have the same composition andmolecular weight but differ in physical and/or chemical properties. Thestructural difference may be in constitution (geometric isomers) or inthe ability to rotate the plane of polarized light (stereoisomers). Withregard to stereoisomers, the compounds of Formula I may have one or moreasymmetric carbon atom and may occur as racemates, racemic mixtures andas individual enantiomers or diastereomers.

A “patient” or “subject” is a mammal, e.g., a human, mouse, rat, guineapig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey,chimpanzee, baboon or rhesus.

In another embodiment of the disclosure are described compounds of theFormula IA:

and pharmaceutically acceptable salts, prodrugs, solvates, hydrates,tautomers or isomer thereof; where R, L, X¹, X², X³, X⁴, Y¹, Y³, and Y⁴are defined as above in Formula I.

In another embodiment of the compounds of Formula IA, X⁴ is CR¹R².

In another embodiment of the compounds of Formula IA, X¹ is NR³, O, orC═O.

In another embodiment of the compounds of Formula IA, X¹ is O.

In another embodiment of the compounds of Formula IA, X¹ is O and X⁴ isCR¹R².

In some embodiments of the disclosure, the compounds of Formula IA maybe of the Formula IA-1:

For instance, in some embodiments of Formula IA-1, the compounds can beof the Formula IA-1a, Formula IA-1b, or Formula IA-1c:

In other embodiments of the compounds of Formula IA, the compound is ofthe Formula IA-2:

In yet other another embodiments of the compounds of Formula IA, thecompound is of the Formula IA-3:

In yet other embodiments of the compounds of Formula IA, the compound isof the Formula IA-4:

In yet other another embodiments of the compounds of Formula IA, thecompound is of the Formula IA-5:

In yet other another embodiments of the compounds of Formula IA, thecompound is of the Formula IA-6:

In yet other another embodiments of the compounds of Formula IA, thecompound is of the Formula IA-7:

In other embodiments of the compounds of Formula IA, the compound mayalso be of the Formula IA-8:

In other embodiments of the compounds of Formula IA, the compound is ofthe Formula IA-9:

In a further embodiment of the compounds of Formula IA, the compound isalso of the Formula IA-10:

In another embodiment of the compounds of Formula IA, the compound is ofthe Formula IA-11:

In one embodiment of the disclosure are also disclosed compounds of theFormula IB:

and pharmaceutically acceptable salts, prodrugs, solvates, hydrates,enantiomers and isomers thereof where R, L, X¹, X², X³, X⁴, Y¹, Y², andY⁴ are defined as above in Formula I.

In one embodiment of the compounds of Formula IB, X⁴ is CR¹R².

In another embodiment of the compounds of Formula IB, X¹ is NR³, O, orC═O.

In another embodiment of the compounds of Formula IB, X¹ is O.

In another embodiment of the compounds of Formula IB, X¹ is O and X⁴ isCR¹R².

In another embodiment of the compounds of Formula IB, X¹ is N, X² isC═O, and X⁴ is CR¹R².

In some embodiments of the disclosure, the compounds of Formula IB, maybe of the Formula IB-1:

In other embodiments of the compounds of Formula IB, the compound is ofthe Formula IB-2:

In yet other embodiments of the compounds of Formula IB, the compound isof the Formula (IB-3):

In other embodiments of the compounds of Formula IB, the compound mayalso be of the Formula IB-4:

In other embodiments of the compounds of Formula IB, the compound is ofthe Formula (IB-5):

In some embodiments of Formula (I), X¹ is O. In another embodiment, X¹is O and X² is CR¹R². In yet another embodiment, X¹ is O, X² is CR¹R²,and X³ is CR¹R². In another embodiment, X¹ is O, X² is CR¹R², X³ isCR^(1′)R^(2′), and X⁴ is CR¹R². In yet another embodiment, X¹ is O, X²is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², and Y¹ is CR¹. In anotherembodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹is CR¹, and Y³ is CR¹. In yet another embodiment, X¹ is O, X² is CR¹R²,X³ is CR¹R², X⁴ is CR¹R², Y¹ is CR¹, Y³ is CR¹, and Y⁴ is CR¹. Inanother embodiment, X¹ is O, X² is CR¹R², X³ is CR¹R², X⁴ is CR¹R², Y¹is CR¹, Y³ is CR¹, Y⁴ is CR¹, and Y² is C. In yet another embodiment, X¹is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ isCR¹, Y⁴ is CR¹, Y² is C, and L is —C(O)—. In another embodiment, X¹ isO, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ is CR¹,Y⁴ is CR¹, Y² is C, L is —C(O)—, and R^(1′) is H. In yet anotherembodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹is CR¹, Y³ is CR¹, Y⁴ is CR¹, Y² is C, L is —C(O)—, R^(1′) is H, andR^(2′) is aryl or heteroaryl containing 1 to 5 heteroatoms selected fromthe group consisting of N, S, P, and O, wherein the aryl or heteroarylis optionally substituted with one or more substituents selected fromhalogen or —R³.

In some embodiments of Formula (I), R is —C₁-C₆ alkyl, —C₄-C₈cycloalkenyl, —C₃-C₈ cycloalkyl, —C₅-C₁₂ spirocycle, heterocyclyl,spiroheterocyclyl, aryl, or heteroaryl containing 1 to 5 heteroatomsselected from the group consisting of N, S, P, and O, wherein eachalkyl, cycloalkenyl, cycloalkyl, spirocycle, heterocyclyl,spiroheterocyclyl, aryl, or heteroaryl is optionally substituted withone or more —OH, halogen, oxo, —NO₂, —CN, —R¹, —R², —OR³, —NHR³, —NR³R⁴,—S(O)₂NR³R⁴, —S(O)₂R¹, —C(O)R¹, or —CO₂R¹, —NR³S(O)₂R¹, —S(O)R¹,—S(O)NR³R⁴, —NR³S(O)R¹, heterocycle, aryl, or heteroaryl containing 1 to5 heteroatoms selected from the group consisting of N, S, P, and O, withthe proviso that R is not bound to L via a nitrogen atom.

In some embodiments of Formula (I), R¹ and R² may combine with the atomto which they are both attached to form a spirocycle. In anotherembodiment, R¹ and R² combine with the atom to which they are bothattached to form a spiroheterocycle. In another embodiment, R¹ and R²combine with the atom to which they are both attached to form aspirocycloalkenyl.

In some embodiments of Formula (I), R¹ and R², when on adjacent atoms,combine to form a heterocycle. In another embodiment, R¹ and R², when onadjacent atoms, combine to form a cycloalkyl. In yet another embodiment,R¹ and R², when on adjacent atoms, combine to form a cycloalkenyl. Inanother embodiment, R¹ and R², when on adjacent atoms, combine to forman aryl. In yet another embodiment, R¹ and R², when on adjacent atoms,combine to form a heteroaryl containing 1 to 5 heteroatoms selected fromthe group consisting of N, S, P, and O.

In some embodiments of Formula (I), R¹ and R², when on non-adjacentatoms, combine to form a bridging cycloalkyl. In another embodiment, R¹and R², when on non-adjacent atoms, combine to form a bridgingcycloalkenyl. In yet another embodiment, R¹ and R², when on non-adjacentatoms, combine to form a heterocycloalkyl.

In some embodiments of Formula (I), n is 1 to 6. In another embodiment,n is 0 to 5. In yet another embodiment, n is 0 to 4. In yet anotherembodiment, n is 1 to 4. In another embodiment, n is 0 to 3. In yetanother embodiment, n is 0 to 2. In yet another embodiment, n is 0 or 1.In another embodiment, n is 1 or 2.

In some embodiments of Formula (I), m is 1 to 6. In another embodiment,m is 1 to 5. In yet another embodiment, m is 1 to 4. In yet anotherembodiment, m is 1 to 3. In another embodiment, m is 1 or 2. In yetanother embodiment, m is 2 or 3. In yet another embodiment, m is 2 to 4.

In some embodiments of Formula (I), X⁴, X², and X¹ are not allsimultaneously CR¹R².

In some embodiments of Formula (I), X¹ is O, X² is CR¹R², and X⁴ isCR¹R². In another embodiment, X² is C═O, X⁴ is C═O, and X¹ is CR¹R². Inyet another embodiment, X¹ is NR³, X² is C═O, and X⁴ is CR¹R².

Non-limiting illustrative compounds of the disclosure include:

-   (S)—N-hydroxy-3-phenyl-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N-hydroxy-3-phenyl-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-(oxetane-3-carbonyl)-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (3S)-4-(8-oxabicyclo[3.2.1]octane-3-carbonyl)-N-hydroxy-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-4-(4-fluorotetrahydro-2H-pyran-4-carbonyl)-N-hydroxy-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-4-(cyclohexanecarbonyl)-N-hydroxy-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-4-(cyclopentanecarbonyl)-N-hydroxy-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-4-(cyclobutanecarbonyl)-N-hydroxy-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-nicotinoyl-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-isonicotinoyl-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-4-(1-acetylpiperidine-4-carbonyl)-N-hydroxy-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-phenyl-4-((S)-tetrahydro-2H-pyran-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-phenyl-4-((R)-tetrahydro-2H-pyran-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-phenyl-4-((S)-tetrahydrofuran-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-phenyl-4-((R)-tetrahydrofuran-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-((1s,4R)-4-methoxycyclohexane-1-carbonyl)-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-((1r,4S)-4-methoxycyclohexane-1-carbonyl)-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-(1-methylpiperidine-4-carbonyl)-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-(1-methoxycyclopropane-1-carbonyl)-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-(2-methoxy-2-methylpropanoyl)-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-phenyl-4-pivaloyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-phenyl-4-picolinoyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-isobutyryl-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-(4-methyltetrahydro-2H-pyran-4-carbonyl)-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-(1-methoxycyclohexane-1-carbonyl)-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-3-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-3-(3-fluorophenyl)-N-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-3-(p-tolyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-3-(4-chlorophenyl)-N-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-3-(3-chlorophenyl)-N-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-3-(4-fluorophenyl)-N-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-3-(o-tolyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N-hydroxy-3-(pyridin-3-yl)-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-(pyridin-3-yl)-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-3-(2-fluorophenyl)-N-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)-3-(2-fluorophenyl)-N-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-3-(2-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-3-(2-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-3-(3-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-3-(3-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-4-acetyl-N-hydroxy-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-4-(4-fluorobenzoyl)-N-hydroxy-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-(1-(methoxymethyl)cyclopropane-1-carbonyl)-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;    and-   (3S)—N-hydroxy-3-phenyl-4-(tetrahydrofuran-2-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide.

In other embodiments, illustrative compounds of Formula (I) includewithout limitations:

-   S)—N-hydroxy-4-(4-methyltetrahydro-2H-pyran-4-carbonyl)-3-(o-tolyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-(4-methyltetrahydro-2H-pyran-4-carbonyl)-3-(3-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N-hydroxy-4-(4-methyltetrahydro-2H-pyran-4-carbonyl)-3-(3-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-3-(3-fluorophenyl)-N-hydroxy-4-(4-methyltetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)-3-(3-fluorophenyl)-N-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)-3-(3-fluorophenyl)-N-hydroxy-4-(4-methyltetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-(4-methyltetrahydro-2H-pyran-4-carbonyl)-3-(2-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N-hydroxy-4-(4-methyltetrahydro-2H-pyran-4-carbonyl)-3-(2-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-3-(2-fluorophenyl)-N-hydroxy-4-(4-methyltetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)-3-(2-fluorophenyl)-N-hydroxy-4-(4-methyltetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-(4-methyltetrahydro-2H-pyran-4-carbonyl)-3-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-(4-methyltetrahydro-2H-pyran-4-carbonyl)-3-(p-tolyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-3-(4-chlorophenyl)-N-hydroxy-4-(4-methyltetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-3-(3-chlorophenyl)-N-hydroxy-4-(4-methyltetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-3-(4-fluorophenyl)-N-hydroxy-4-(4-methyltetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-(quinoxalin-6-yl)-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-(quinolin-6-yl)-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-(quinolin-7-yl)-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-(naphthalen-2-yl)-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N-hydroxy-3-(quinoxalin-6-yl)-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N-hydroxy-3-(quinolin-6-yl)-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N-hydroxy-3-(quinolin-7-yl)-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N-hydroxy-3-(naphthalen-2-yl)-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-(quinoxalin-5-yl)-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-(quinolin-5-yl)-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-(quinolin-8-yl)-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-(naphthalen-1-yl)-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N-hydroxy-3-(quinoxalin-5-yl)-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N-hydroxy-3-(quinolin-5-yl)-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N-hydroxy-3-(quinolin-8-yl)-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N-hydroxy-3-(naphthalen-1-yl)-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (3S)—N-hydroxy-5-methyl-3-phenyl-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (3S)—N-hydroxy-5-methyl-4-(4-methyltetrahydro-2H-pyran-4-carbonyl)-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-6-fluoro-N-hydroxy-3-phenyl-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-6-fluoro-N-hydroxy-4-(4-methyltetrahydro-2H-pyran-4-carbonyl)-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-(3-methoxy-2,2-dimethylpropanoyl)-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-(3-methoxy-3-methylbutanoyl)-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-(3-hydroxy-3-methylbutanoyl)-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-phenyl-4-(3-phenylpropanoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-phenyl-4-(4,4,4-trifluorobutanoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-phenyl-4-(3-(trifluoromethoxy)propanoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-phenyl-4-(3-(tetrahydro-2H-pyran-4-yl)propanoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-4-(3-(dimethylamino)propanoyl)-N-hydroxy-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;    and-   (S)-4-(2,2-dimethyl-3-(tetrahydro-2H-pyran-4-yl)propanoyl)-N-hydroxy-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide.

In another embodiment of the disclosure, the compounds of Formula I areenantiomers. In some embodiments the compounds are the (S)-enantiomer.In other embodiments the compounds are the (R)-enantiomer. In someembodiment, the (R)- or (S)-enantiomeric configuration may be assignedto each molecule. In other embodiments, the (R)- or (S)-enantiomericconfiguration may not be assigned to the molecules despite theenantiomeric purification or separation of the molecules. In yet otherembodiments, the compounds of Formula I may be (+) or (−) enantiomers.

It should be understood that all isomeric forms are included within thepresent disclosure, including mixtures thereof. If the compound containsa double bond, the substituent may be in the E or Z configuration or cisor trans configuration. If the compound contains a disubstitutedcycloalkyl, the cycloalkyl substituent may have a cis- or transconfiguration. All tautomeric forms are also intended to be included. Insome embodiment, the cis or trans configuration may be assigned to eachmolecule. In other embodiments, the cis or trans configuration may notbe assigned to the molecules despite the chemical purification orseparation of the diastereomers.

Methods of Synthesizing the Disclosed Compounds

The compounds of the present disclosure may be made by a variety ofmethods, including standard chemistry. Suitable synthetic routes aredepicted in the schemes given below.

The compounds of Formula I may be prepared by methods known in the artof organic synthesis as set forth in part by the following syntheticschemes and examples. In the schemes described below, it is wellunderstood that protecting groups for sensitive or reactive groups areemployed where necessary in accordance with general principles orchemistry. Protecting groups are manipulated according to standardmethods of organic synthesis (T. W. Greene and P. G. M. Wuts,“Protective Groups in Organic Synthesis”, Third edition, Wiley, New York1999). These groups are removed at a convenient stage of the compoundsynthesis using methods that are readily apparent to those skilled inthe art. The selection processes, as well as the reaction conditions andorder of their execution, shall be consistent with the preparation ofcompounds of Formula I.

Those skilled in the art will recognize if a stereocenter exists in thecompounds of Formula I. Accordingly, the present disclosure includesboth possible stereoisomers (unless specified in the synthesis) andincludes not only racemic compounds but the individual enantiomersand/or diastereomers as well. When a compound is desired as a singleenantiomer or diastereomer, it may be obtained by stereospecificsynthesis or by resolution of the final product or any convenientintermediate. Resolution of the final product, an intermediate, or astarting material may be affected by any suitable method known in theart. See, for example, “Stereochemistry of Organic Compounds” by E. L.Eliel, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994).

The compounds described herein may be made from commercially availablestarting materials or synthesized using known organic, inorganic, and/orenzymatic processes.

Preparation of Compounds

The compounds of the present disclosure can be prepared in a number ofways well known to those skilled in the art of organic synthesis. By wayof example, compounds of the present disclosure can be synthesized usingthe methods described below, together with synthetic methods known inthe art of synthetic organic chemistry, or variations thereon asappreciated by those skilled in the art. These methods include, but arenot limited, to those methods described below. Compounds of the presentdisclosure can be synthesized by following the steps outlined in GeneralSchemes 1, 2, 3, 4, and 5 which comprise different sequences ofassembling intermediates 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2m,2n, 2o, 2p, 2q, 2r, 2s, 2t, 2u, 2v, 2w, 2x, 2y, 2z, 2aa, 2bb, and 2cc.Starting materials are either commercially available or made by knownprocedures in the reported literature or as illustrated.

wherein L, R, R¹, R², R^(1′), R^(2′), Y¹ and Y² are defined as inFormula (I).

The general way of preparing target molecules of Formula (I) by usingintermediates 2a, 2b, 2c, 2d, and 2e is outlined in General Scheme 1.Nucleophilic addition of alcohol 2b to Intermediate 2a using a base,e.g., potassium carbonate (K₂CO₃), in a solvent, e.g., acetonitrile(MeCN), provides Intermediate 2c. Cyclization of Intermediate 2c in thepresence of a catalytic amount of a metal catalyst, e.g., copper iodide(CuI), palladium acetate (Pd(OAc)₂), etc., and a base, e.g., potassiumcarbonate (K₂CO₃), in a solvent, e.g., isopropanol (i-PrOH), optionallyat elevated temperature provides Intermediate 2d. Acylation ofIntermediate 2d with an acyl halide in the presence of a base, e.g.,sodium hydride (NaH), and optionally at elevated temperatures providesIntermediate 2e. Alternatively, coupling of a carboxylic acid withIntermediate 2d under standard coupling conditions using a couplingreagent, e.g.,1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxidehexafluoro-phosphate (HATU), orO-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate(HBTU), and a base, e.g., triethylamine or N,N-diisopropylethylamine(DIPEA), in a solvent, e.g., dichloromethane or DMF providesIntermediate 2e. Intermediate 2e can also be obtained by reacting 2dwith a carboxylic acid and an activating agent, e.g.,4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride(DMTMM), in a solvent, e.g., dimethylformamide (DMF). Treatment ofIntermediate 2e with hydroxylamine and a base, e.g., aqueous sodiumhydroxide (aq. NaOH) in a solvent, e.g., tetrahydrofuran (THF) and/ormethanol (MeOH), provides compounds of Formula (I).

wherein L, R, R^(1′), and R^(2′) are defined as in Formula (I).

The general way of preparing target molecules of Formula (I) by usingintermediates 2f, 2g, 2h, 2i, 2j, and 2k is outlined in General Scheme2. Nucleophilic addition of amine 2g to Intermediate 2f using a base,e.g., N,N-diisopropylethylamine (DIEA), and in a solvent, e.g., MeCN,dichloromethane (DCM), or DMF, provides Intermediate 2h. Protection ofthe amine group in intermediate 2h with a typical acid labile protectinggroup (e.g., t-butoxycarbonyl (Boc)) using an alkyl chloride and4-Dimethylaminopyridine (DMAP), in a solvent e.g., DCM ortetrahydrofuran (THF), followed by hydrogenation in the presence of ametal catalyst, e.g., palladium on carbon, and hydrogen (H₂) gas in asolvent, e.g., DCM, provides Intermediate 2i. Cyclization ofIntermediate 2i in the presence of a base, e.g., potassium carbonate(K₂CO₃), and in a solvent, e.g., isopropanol (i-PrOH), optionally atelevated temperatures provides Intermediate 2j. Acylation ofIntermediate 2j with an acyl halide in the presence of a base, e.g.,sodium hydride (NaH), and optionally at elevated temperatures providesIntermediate 2k. Alternatively, coupling of a carboxylic acid withIntermediate 2j under standard coupling conditions using a couplingreagent, e.g.,1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxidehexafluoro-phosphate (HATU), orO-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate(HBTU), and a base, e.g., triethylamine or N,N-diisopropylethylamine(DIPEA), in a solvent, e.g., dichloromethane or DMF providesIntermediate 2k. Intermediate 2k can also be obtained by reacting 2jwith a carboxylic acid and an activating agent, e.g.,4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride(DMTMM), in a solvent, e.g., dimethylformamide (DMF). Treatment ofIntermediate 2k with hydroxylamine and a base, e.g., aqueous sodiumhydroxide (aq. NaOH) in a solvent, e.g., tetrahydrofuran (THF) and/ormethanol (MeOH), provides compounds of Formula (I).

wherein L, R, R^(1′), and R^(2′) are defined as in Formula (I).

The general way of preparing target molecules of Formula (I) by usingintermediates 2m, 2n, 2o, 2p, and 2q, is outlined in General Scheme 3.Sulfonylation of alcohol 2n with Intermediate 2m in the presence of ametal oxide, e.g., MgO, and in a solvent, e.g., THF and or water (H₂O),provides Intermediate 2o. Cyclization of Intermediate 2o in the presenceof a base, e.g., sodium methoxide (NaOMe), and in a solvent, e.g.,methanol (MeOH), i-PrOH, etc., provides Intermediate 2p. Acylation ofIntermediate 2p with an acyl halide in the presence of a base, e.g.,sodium hydride (NaH), and optionally at elevated temperatures providesIntermediate 2q. Alternatively, coupling of a carboxylic acid withIntermediate 2p under standard coupling conditions using a couplingreagent, e.g.,1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxidehexafluoro-phosphate (HATU), orO-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate(HBTU), and a base, e.g., triethylamine or N,N-diisopropylethylamine(DIPEA), in a solvent, e.g., dichloromethane or DMF providesIntermediate 2q. Intermediate 2q can also be obtained by reacting 2pwith a carboxylic acid and an activating agent, e.g.,4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride(DMTMM), in a solvent, e.g., dimethylformamide (DMF). Treatment ofIntermediate 2q with hydroxylamine and a base, e.g., aqueous sodiumhydroxide (aq. NaOH), in a solvent, e.g., tetrahydrofuran (THF) and/ormethanol (MeOH), provides compounds of Formula (I).

wherein L, R, R^(1′), and R^(2′) are defined as in Formula (I).

The general way of preparing target molecules of Formula (I) by usingintermediates 2r, 2s, 2t, 2u, and 2v, is outlined in General Scheme 4.Intermediate 2t can be obtained by alkylation of 2s with phenol 2r usinga Mitsunobu reagent (e.g., diethyl azodicarboxylate (DEAD) ordiisopropyl azodicarboxylate (DIAD)), and triphenyl phosphine in asolvent, e.g., tetrahydrofuran (THF), dichloromethane (DCM).Deprotection of intermediate 2t using a strong acid such astrifluoroacetic acid (TFA) in a solvent, e.g., dichloromethane (DCM),followed by cyclization in the presence of a base, e.g., triethylamine(Et₃N), and optionally in a solvent, e.g., THF, MeOH, etc., at elevatedtemperature provides Intermediate 2u. Acylation of Intermediate 2u withan acyl halide in the presence of a base, e.g., sodium hydride (NaH),and optionally at elevated temperatures provides Intermediate 2v.Alternatively, coupling of a carboxylic acid with Intermediate 2u understandard coupling conditions using a coupling reagent, e.g.,1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxidehexafluoro-phosphate (HATU), orO-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate(HBTU), and a base, e.g., triethylamine or N,N-diisopropylethylamine(DIPEA), in a solvent, e.g., dichloromethane or DMF providesIntermediate 2v. Intermediate 2v can also be obtained by reacting 2uwith a carboxylic acid and an activating agent, e.g.,4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride(DMTMM), in a solvent, e.g., dimethylformamide (DMF). Treatment ofIntermediate 2v with hydroxylamine and a base, e.g., aqueous sodiumhydroxide (aq. NaOH) in a solvent, e.g., tetrahydrofuran (THF) and/ormethanol (MeOH), provides compounds of Formula (I).

wherein L, R, R^(1′), and R^(2′) are defined as in Formula (I).

The general way of preparing target molecules of Formula (I) by usingintermediates 2w, 2x, 2y, 2z, 2aa, 2bb, and 2cc, is outlined in GeneralScheme 5. Alkylation of phenol 2w with Intermediate 2x using potassiumiodide (KI) and a base, e.g., potassium carbonate (K₂CO₃), in a solvent,e.g., MeCN, THF, etc., provides Intermediate 2y. Deprotection ofIntermediate 2y using a strong acid such as trifluoroacetic acid (TFA)in a solvent, e.g., dichloromethane (DCM) followed by cyclization viaintramolecular reductive amination in the presence of sodium borohydrideor sodium cyanoborohydride in a solvent, e.g., THF, MeOH, etc., providesIntermediate 2z. Protection of the amine group in intermediate 2z with atypical acid labile protecting group (e.g., t-butoxycarbonyl (Boc))using an alkyl chloride and optionally 4-DMAP in a solvent e.g., DCM ortetrahydrofuran (THF), followed by carbonylation in the presence of ametal catalyst, e.g.,[1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride, andcarbon monoxide (CO) gas in a solvent, e.g., DCM, provides Intermediate2aa. Deprotection of intermediate 2aa using a strong acid such astrifluoroacetic acid (TFA) in a solvent, e.g., dichloromethane (DCM)provides Intermediate 2bb. Acylation of Intermediate 2bb with an acylhalide in the presence of a base, e.g., sodium hydride (NaH), andoptionally at elevated temperatures provides Intermediate 2cc.Alternatively, coupling of a carboxylic acid with Intermediate 2bb understandard coupling conditions using a coupling reagent, e.g.,1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b)]pyridinium3-oxidehexafluoro-phosphate (HATU), orO-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate(HBTU), and a base, e.g., triethylamine or N,N-diisopropylethylamine(DIPEA), in a solvent, e.g., dichloromethane or DMF providesIntermediate 2cc. Intermediate 2cc can also be obtained by reacting 2bbwith a carboxylic acid and an activating agent, e.g.,4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride(DMTMM), in a solvent, e.g., dimethylformamide (DMF). Treatment ofIntermediate 2cc with hydroxylamine and a base, e.g., aqueous sodiumhydroxide (aq. NaOH), in a solvent, e.g., tetrahydrofuran (THF) and/ormethanol (MeOH), provides compounds of Formula (I).

Methods of Using the Disclosed Compounds

Another aspect of the disclosure relates to a method of treating adisease associated with HDAC, e.g., HDAC6, modulation in a subject inneed thereof. The method involves administering to a patient in need oftreatment for diseases or disorders associated with HDAC, e.g., HDAC6,modulation an effective amount of a compound of Formula I. In anembodiment, the disease can be, but is not limited to, cancer,neurodegenerative disease, neurodevelopmental disease, inflammatory orautoimmune disease, infection, metabolic disease, hematologic disease,or cardiovascular disease.

Another aspect of the disclosure is directed to a method of inhibitingan HDAC, e.g., HDAC6. The method involves administering to a patient inneed thereof an effective amount of Formula I.

The present disclosure relates to compositions capable of modulating theactivity of (e.g., inhibiting) HDACs, for instance HDAC6. The presentdisclosure also relates to the therapeutic use of such compounds.

One therapeutic use of the compounds of the present disclosure is totreat proliferative diseases or disorders such as cancer. Cancer can beunderstood as abnormal or unregulated cell growth within a patient andcan include, but is not limited to lung cancer, ovarian cancer, breastcancer, prostate cancer, pancreatic cancer, hepatocellular cancer, renalcancer and leukemias such as acute myeloid leukemia and acutelymphoblastic leukemia. Additional cancer types include T-cell lymphoma(e.g., cutaneous T-cell lymphoma, peripheral T-cell lymphoma), andmultiple myeloma.

One therapeutic use of the compounds of the present disclosure is totreat neurological diseases or disorders or neurodegeneration.Neurological disorders are understood as disorders of the nervous system(e.g., the brain and spinal cord). Neurological disorders orneurodegenerative diseases can include, but are not limited to epilepsy,attention deficit disorder (ADD), Alzheimer's disease, Parkinson'sDisease, Huntington's Disease, amyotrophic lateral sclerosis, spinalmuscular atrophy, essential tremor, central nervous system trauma causedby tissue injury, oxidative stress-induced neuronal or axomaldegeneration, and multiple sclerosis.

Another therapeutic use of the compounds of the present disclosure is totreat neurodevelopmental disorders. Neurodevelopmental disorders caninclude, but are not limited to, Rett syndrome.

Another therapeutic use of the compounds of the present disclosure isalso to treat inflammatory diseases or disorders. Inflammation can beunderstood as a host's response to an initial injury or infection.Symptoms of inflammation can include but are not limited to redness,swelling, pain, heat and loss of function. Inflammation may be caused bythe upregulation of pro-inflammatory cytokines such as IL-1β, andincreased expression of the FOXP3 transcription factor.

Another therapeutic use of the compounds of the present disclosure isalso to treat autoimmune diseases or disorders. Autoimmune disorders areunderstood as disorders wherein a host's own immune system responds totissues and substances occurring naturally in the host's body.Autoimmune diseases can include, but are not limited to Rheumatoidarthritis, spondylitis arthritis, psoriatic arthritis, multiplesclerosis, systemic lupus erythematosus, inflammatory bowel disease,graft versus host disease, transplant rejection, fibrotic disease,Crohn's Disease, type-1 diabetes, Eczema, and psoriasis.

Another therapeutic use of the compounds of the present disclosure isalso to treat infectious diseases or disorders. Infections or infectiousdiseases are caused by the invasion of a foreign pathogen. The infectionmay be caused by, for instance, a bacteria, a fungus, or virus. Forexample, a bacterial infection may be caused by a E. coli.

Yet another therapeutic use of the compounds of the present disclosureis also to treat metabolic diseases or disorders. Metabolic diseases canbe characterized as abnormalities in the way that a subject storesenergy. Metabolic disorders can include, but are not limited tometabolic syndrome, diabetes, obesity, high blood pressure, and heartfailure.

Yet another therapeutic use of the compounds of the present disclosureis also to treat hematologic disorders. Hematologic diseases primarilyaffect the blood. Hematologic disorders can include, but are not limitedto anemia, lymphoma, and leukemia.

Yet another therapeutic use of the compounds of the present disclosureis also to treat cardiovascular diseases or disorders. Cardiovasculardiseases affect the heart and blood vessels of a patient. Exemplaryconditions include but are not limited to cardiovascular stress,pressure overload, chronic ischemia, infarction-reperfusion injury,hypertension, atherosclerosis, peripheral artery disease, and heartfailure.

Another aspect of the present disclosure relates to a compound ofFormula (I), or a pharmaceutically acceptable salt, hydrate, solvate,prodrug, stereoisomer, or tautomer thereof, for use in treating orpreventing a disease associated with HDAC6 modulation. In someembodiments, the disease is cancer, neurodegenerative disease,neurodevelopmental disorder, inflammatory or autoimmune disease,infection, metabolic disease, hematologic disease, or cardiovasculardisease. In some embodiments, the compound inhibits a histonedeacetylase. In another embodiment, the compound inhibits azinc-dependent histone deacetylase. In another embodiment, the compoundinhibits the HDAC6 isozyme zinc-dependent histone deacetylase.

In another aspect, the present disclosure relates to the use of acompound of Formula (I), or a pharmaceutically acceptable salt, hydrate,solvate, prodrug, stereoisomer, or tautomer thereof, in the manufactureof a medicament for treating or preventing a disease associated withHDAC6 modulation. In some embodiments, the disease is cancer,neurodegenerative disease, neurodevelopmental disorder, inflammatory orautoimmune disease, infection, metabolic disease, hematologic disease,or cardiovascular disease. In some embodiments, the compound inhibits ahistone deacetylase. In another embodiment, the compound inhibits azinc-dependent histone deacetylase. In another embodiment, the compoundinhibits the HDAC6 isozyme zinc-dependent histone deacetylase.

In some embodiments, the cancer is cutaneous T-cell lymphoma, peripheralT-cell lymphoma, multiple myeloma, leukemia, lung, ovarian, breast,prostate, pancreatic, hepatocellular or renal cancer. In otherembodiments, the neurodegenerative disease is Alzheimer's, Huntington's,Parkinson's, Amyotrophic Lateral Sclerosis, or spinal muscular atrophy.In other embodiments, the neurodevelopmental disorder is Rett syndrome.In yet other embodiments, the inflammatory or autoimmune disease isrheumatoid arthritis, spondylitis arthritis, psoriatic arthritis,psoriasis, multiple sclerosis, systemic lupus erythematosus,inflammatory bowel diseases, graft versus host disease, transplantrejection or fibrotic disease.

The disclosed compound can be administered in effective amounts to treator prevent a disorder and/or prevent the development thereof insubjects.

Administration of the disclosed compounds can be accomplished via anymode of administration for therapeutic agents. These modes includesystemic or local administration such as oral, nasal, parenteral,transdermal, subcutaneous, vaginal, buccal, rectal or topicaladministration modes.

Depending on the intended mode of administration, the disclosedcompositions can be in solid, semi-solid or liquid dosage form, such as,for example, injectables, tablets, suppositories, pills, time-releasecapsules, elixirs, tinctures, emulsions, syrups, powders, liquids,suspensions, or the like, sometimes in unit dosages and consistent withconventional pharmaceutical practices. Likewise, they can also beadministered in intravenous (both bolus and infusion), intraperitoneal,subcutaneous or intramuscular form, all using forms well known to thoseskilled in the pharmaceutical arts.

Illustrative pharmaceutical compositions are tablets and gelatincapsules comprising a Compound of the Disclosure and a pharmaceuticallyacceptable carrier, such as a) a diluent, e.g., purified water,triglyceride oils, such as hydrogenated or partially hydrogenatedvegetable oil, or mixtures thereof, corn oil, olive oil, sunflower oil,safflower oil, fish oils, such as EPA or DHA, or their esters ortriglycerides or mixtures thereof, omega-3 fatty acids or derivativesthereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose,sodium, saccharin, glucose and/or glycine; b) a lubricant, e.g., silica,talcum, stearic acid, its magnesium or calcium salt, sodium oleate,sodium stearate, magnesium stearate, sodium benzoate, sodium acetate,sodium chloride and/or polyethylene glycol; for tablets also; c) abinder, e.g., magnesium aluminum silicate, starch paste, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesiumcarbonate, natural sugars such as glucose or beta-lactose, cornsweeteners, natural and synthetic gums such as acacia, tragacanth orsodium alginate, waxes and/or polyvinylpyrrolidone, if desired; d) adisintegrant, e.g., starches, agar, methyl cellulose, bentonite, xanthangum, alginic acid or its sodium salt, or effervescent mixtures; e)absorbent, colorant, flavorant and sweetener; f) an emulsifier ordispersing agent, such as Tween 80, Labrasol, HPMC, DOSS, caproyl 909,labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex355, gelucire, vitamin E TGPS or other acceptable emulsifier; and/or g)an agent that enhances absorption of the compound such as cyclodextrin,hydroxypropyl-cyclodextrin, PEG400, PEG200.

Liquid, particularly injectable, compositions can, for example, beprepared by dissolution, dispersion, etc. For example, the disclosedcompound is dissolved in or mixed with a pharmaceutically acceptablesolvent such as, for example, water, saline, aqueous dextrose, glycerol,ethanol, and the like, to thereby form an injectable isotonic solutionor suspension. Proteins such as albumin, chylomicron particles, or serumproteins can be used to solubilize the disclosed compounds.

The disclosed compounds can be also formulated as a suppository that canbe prepared from fatty emulsions or suspensions; using polyalkyleneglycols such as propylene glycol, as the carrier.

The disclosed compounds can also be administered in the form of liposomedelivery systems, such as small unilamellar vesicles, large unilamellarvesicles and multilamellar vesicles. Liposomes can be formed from avariety of phospholipids, containing cholesterol, stearylamine orphosphatidylcholines. In some embodiments, a film of lipid components ishydrated with an aqueous solution of drug to a form lipid layerencapsulating the drug, as described in U.S. Pat. No. 5,262,564.

Disclosed compounds can also be delivered by the use of monoclonalantibodies as individual carriers to which the disclosed compounds arecoupled. The disclosed compounds can also be coupled with solublepolymers as targetable drug carriers. Such polymers can include, but arenot limited to polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacryl-amidephenol,polyhydroxyethylaspanamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the disclosedcompounds can be coupled to a class of biodegradable polymers useful inachieving controlled release of a drug, for example, polylactic acid,polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters,polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked oramphipathic block copolymers of hydrogels. In one embodiment, disclosedcompounds are not covalently bound to a polymer, e.g., a polycarboxylicacid polymer, or a polyacrylate.

Parental injectable administration is generally used for subcutaneous,intramuscular or intravenous injections and infusions. Injectables canbe prepared in conventional forms, either as liquid solutions orsuspensions or solid forms suitable for dissolving in liquid prior toinjection.

Another aspect of the disclosure relates to a pharmaceutical compositioncomprising a compound of Formula I and a pharmaceutically acceptablecarrier. The pharmaceutically acceptable carrier can further include anexcipient, diluent, or surfactant.

Compositions can be prepared according to conventional mixing,granulating or coating methods, respectively, and the presentpharmaceutical compositions can contain from about 0.1% to about 99%,from about 5% to about 90%, or from about 1% to about 20% of thedisclosed compound by weight or volume.

The dosage regimen utilizing the disclosed compound is selected inaccordance with a variety of factors including type, species, age,weight, sex and medical condition of the patient; the severity of thecondition to be treated; the route of administration; the renal orhepatic function of the patient; and the particular disclosed compoundemployed. A physician or veterinarian of ordinary skill in the art canreadily determine and prescribe the effective amount of the drugrequired to prevent, counter or arrest the progress of the condition.

Effective dosage amounts of the disclosed compounds, when used for theindicated effects, range from about 0.5 mg to about 5000 mg of thedisclosed compound as needed to treat the condition. Compositions for invivo or in vitro use can contain about 0.5, 5, 20, 50, 75, 100, 150,250, 500, 750, 1000, 1250, 2500, 3500, or 5000 mg of the disclosedcompound, or, in a range of from one amount to another amount in thelist of doses. In one embodiment, the compositions are in the form of atablet that can be scored.

Without wishing to be bound by any particular theory, the compounds ofthe present disclosure can inhibit HDACs such as HDAC6 by interactingwith the zinc (Zn²⁺) ion in the protein's active site via the hydroxamicacid group bound to the aromatic ring of the compound. The binding canprevent the zinc ion from interacting with its natural substrates, thusinhibiting the enzyme.

EXAMPLES

The disclosure is further illustrated by the following examples andsynthesis examples, which are not to be construed as limiting thisdisclosure in scope or spirit to the specific procedures hereindescribed. It is to be understood that the examples are provided toillustrate certain embodiments and that no limitation to the scope ofthe disclosure is intended thereby. It is to be further understood thatresort may be had to various other embodiments, modifications, andequivalents thereof which may suggest themselves to those skilled in theart without departing from the spirit of the present disclosure and/orscope of the appended claims.

The present disclosure includes a number of unique features andadvantages compared with other inhibitors of HDAC enzymes, for instanceHDAC6. For instance, the present disclosure features a unique class ofsmall molecule therapeutic agents of Formula I. The compounds weredesigned by using crystal structure information of HDAC ligand-proteincomplexes as well as advanced computational chemistry tools. Thesetechniques led to the development of new chemical scaffolds that wereiteratively refined to optimize key recognition features between theligand and receptor known to be necessary for potency.

Definitions used in the following examples and elsewhere herein are:

-   aq.: aqueous-   Boc: t-butoxycarbonyl-   CDCl₃: deuterated chloroform-   CH₂Cl₂: methylene chloride, dichloromethane-   CuI: copper (I) iodide-   DIEA: diisopropylethylamine-   DMA: dimethylacetamide-   DMC: 2-chloro-1,3-dimethylimidazolinium chloride-   DMF: N,N-dimethylformamide-   DMSO: dimethylsulfoxide-   DMTMM: 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium    chloride-   Et₃N: triethylamine-   EtOAc: ethyl acetate-   EtOH ethanol-   h: hours-   H₂O: water-   HATU:    1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium    3-oxid hexafluorophosphate-   HCl: hydrochloric acid-   K₂CO₃: potassium carbonate-   MeCN: acetonitrile-   MeOH: methanol-   MgSO₄: magnesium sulfate-   min: minutes-   Na₂SO₄: sodium sulfate-   NaOH: sodium hydroxide-   NH₂OH: hydroxylamine-   NH₄HCO₃: ammonium bicarbonate-   NH₄OH ammonium hydroxide-   Pd(dppf)Cl₂:    [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-   Pd(dppf)Cl₂.CH₂Cl₂:    [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane    adduct-   Pd(OAc)₂: palladium(II) acetate-   pet. ether: petroleum ether-   prep-HPLC: preparatory high pressure liquid chromatography-   TFA: trifluoroacetic acid-   THF: tetrahydrofuran-   THP tetrahydropyran

Example 1—Preparation of(S)—N-hydroxy-3-phenyl-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(S)-3-bromo-4-(((2-hydroxy-1-phenylethyl)amino)methyl)benzoate

(S)-2-Amino-2-phenylethan-1-ol (7.5 g, 54.67 mmol, 2 equiv), K₂CO₃ (5.68g, 40.8 mmol, 1.5 equiv), and MeCN (120 mL) were added to a 500-mLround-bottom flask. This was followed by the dropwise addition of asolution of methyl 3-bromo-4-(bromomethyl)benzoate (14 g, 45.46 mmol, 1equiv) in MeCN (130 mL) with stirring at 0° C. The resulting mixture wasstirred overnight at room temperature. The solids were removed byfiltration and the filtrate was concentrated under vacuum. The residuewas purified by silica gel chromatography (EtOAc/pet. ether, 1:1) toafford the title compound as a yellow oil (9 g, 54% yield). MS: (ES,m/z): 364 [M+H]⁺.

Step-2: Methyl(S)-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

A solution of methyl(S)-3-bromo-4-(((2-hydroxy-1-phenylethyl)amino)methyl)benzoate (5 g,13.73 mmol, 1 equiv) in isopropanol (120 mL) were added to a 150-mLsealed tube purged and maintained with an inert atmosphere of nitrogen.This was followed by the addition of K₂CO₃ (2.85 g, 20.47 mmol, 1.5equiv) and CuI (0.78 g, 4.12 mmol, 0.3 equiv). The resulting mixture wasstirred overnight at 110° C. in an oil bath. The reaction was cooled toroom temperature and then concentrated under vacuum. The residue wasdiluted with water (200 mL) and extracted with EtOAc (2×100 mL). Thecombined organic layers were washed with a 30% NH₄OH solution (100 mL)and brine (200 mL), dried over anhydrous Na₂SO₄, filtered, andconcentrated under vacuum. The residue was purified by silica gelchromatography (EtOAc/pet. ether, 1:3 to 1:1) to afford the titlecompound as a yellow solid (1.4 g, 36% yield). MS: (ES, m/z): 284[M+H]⁺.

Step-3: Methyl(S)-3-phenyl-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Oxane-4-carboxylic acid (103 mg, 0.79 mmol, 1.5 equiv), DMF (10 mL) andDMTMM (294 mg, 1.06 mmol, 2 equiv) were added to a 100-mL round-bottomflask and the resulting solution was stirred for 30 min at roomtemperature. Methyl(S)-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (150mg, 0.53 mmol, 1 equiv) was then added. The resulting solution wasstirred overnight at room temperature and then concentrated undervacuum. The resulting residue was purified by silica gel chromatography(EtOAc/pet. ether, 1:10 to 1:1) to afford the title compound as a whitesolid (132 mg, 63% yield). MS: (ES, m/z): 396 [M+H]⁺.

Step-4:(S)—N-Hydroxy-3-phenyl-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepine-8-carboxamide

Methyl(S)-3-phenyl-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(132 mg, 0.33 mmol, 1 equiv), THF/MeOH (4:1, 2.5 mL), NH₂OH (50% inwater, 2205 mg, 33.42 mmol, 100 equiv), and aq. 1N NaOH (0.67 mL, 2equiv) were added to a 25-mL round-bottom flask and the resultingsolution was stirred for 2 h at room temperature. The crude product waspurified by prep-HPLC (Column: XBridge C18 OBD, 5 μm, 19×150 mm; MobilePhase A: Water/0.1% formic acid; Mobile Phase B: MeCN; Detector, UV 254nm) to afford the title compound as a white solid (66.6 mg, 46% yield).¹H-NMR (300 MHz, DMSO-d₆) δ(ppm): 11.22-11.12 (br s, 1H), 7.46-7.21 (m,8H), 5.92-5.68 (m, 1H), 5.24-4.56 (m, 4H), 3.87-3.72 (m, 1H), 3.71-3.66(m, 1H), 3.46-3.25 (m, 1H), 3.21-3.08 (m, 1H), 2.93-2.71 (m, 1H),1.72-1.35 (m, 3H), 1.12-0.81 (m, 1H). MS: (ES, m/z): 397 [M+H]⁺.

TABLE 1 The following compounds were prepared according to the method ofExample 1, using (R)-2-amino-2-phenylethan-1-ol or(S)-2-amino-2-phenylethan-1-ol in Step 1 where appropriate. FoundStructure M + H ¹H-NMR (300 MHz, DMSO-d₆) δ(ppm)

(ES, m/z): 397 [M + H]⁺ 11.20 (br s, 1H), 7.44-7.21 (m, 8H), 5.90-5.87(m, 1H), 5.23-4.58 (m, 4H), 3.89-3.67 (m, 2H), 3.43-3.30 (m, 1H),3.17-3.09 (m, 1H), 2.90-2.72 (m, 1H), 1.68-1.35 (m, 3H), 1.10-0.83 (m,1H)

(ES, m/z): 369 [M + H]⁺ 11.14 (br s, 1H), 9.03 (br s, 1H), 7.39-7.20 (m,8H), 5.90-5.88 (m, 0.5H), 5.23-5.12 (m, 0.5H), 4.98-4.94 (m, 0.5H),4.79-4.50 (m, 5H), 4.45-4.34 (m, 1H), 4.23-4.05 (m, 2H)

(ES, m/z): 423 [M + H]⁺ 11.15 (br s, 1H), 9.02 (br s, 1H), 7.43-7.18 (m,8H), 5.89-5.70 (m, 1H), 5.27-5.22 (m, 0.5H), 4.96-4.95 (m, 1H),4.78-4.46 (m, 2.5H), 4.29-4.27 (m, 1H), 4.07 (s, 1H), 3.10-2.88 (m, 1H),1.80-1.43 (m, 7H)

(ES, m/z): 415 [M + H]⁺ 11.13 (br s, 1H), 9.06 (br, 1H), 7.41-7.22 (m,8H), 5.97- 5.74 (m, 1H), 5.17 (d, J = 20 Hz, 1H), 5.18-4.96 (m, 1H),4.81-4.71 (m, 1H), 4.65-4.49 (m, 1H), 3.85-3.62 (m, 3H), 3.60-3.41 (m,1H), 2.30-1.72 (m, 3H), 1.71- 1.48 (m, 1H)

(ES, m/z): 395 [M + H]⁺ 11.14 (br s, 1H), 9.05 (br s, 1H), 7.43-7.20 (m,8H), 5.91-5.81 (m, 1H), 5.20-5.17 (m, 1H), 4.93-4.91 (m, 1H), 4.71-4.58(m, 2H), 2.51-2.49 (m, 1H), 1.57-1.53 (m, 4H), 1.36-1.00 (m, 6H)

(ES, m/z): 381 [M + H]⁺ 11.15 (br s, 1H), 9.02 (br s, 1H), 7.43-7.21 (m,8H), 5.92-5.87 (m, 1H), 5.25-5.21 (m, 1H), 4.96-4.93 (m, 1H), 4.74-4.58(m, 2H), 3.01-2.90 (m, 1H), 2.05-1.90 (m, 1H), 1.61-1.33 (m, 7H)

(ES, m/z): 367 [M + H]⁺ 11.12 (br s, 1H), 9.02 (br s, 1H), 7.42-7.20 (m,8H), 5.87-5.84 (m, 1H), 4.96-4.92 (m, 1H), 4.68-4.57 (m, 3H), 3.34-3.30(m, 1H), 2.28-2.26 (m, 1H), 2.19-2.14 (m, 1H), 1.88-1.80 (m, 1H),1.77-1.65 (m, 3H)

(ES, m/z): 390 [M + H]⁺ 11.02 (s, 1H), 9.11 (s, 1H), 8.66-8.59 (m, 1H),8.32-8.26 (m, 1H), 7.59-7.25 (m, 9.5H), 6.81-6.79 (m, 0.5H), 5.98- 5.95(m, 0.5H), 5.30-5.21 (m, 1H), 5.12-5.07 (m, 0.5H), 4.83-4.43 (m, 3H)

(ES, m/z): 390 [M + H]⁺ 11.18 (s, 1H), 9.07 (s, 1H), 8.61-8.55 (m, 2H),7.50-7.27 (m, 7.5H), 7.13-7.05 (m, 2H), 6.77-6.75 (m, 0.5H), 5.98- 5.94(m, 0.5H), 5.30-5.26 (m, 0.5H), 5.12-5.06 (m, 1H), 4.79-4.58 (m, 2.5H),4.39-4.34 (m, 0.5H)

(ES, m/z): 438 [M + H]⁺ 11.19 (br s, 1H), 9.09 (m, 1H), 7.47-7.21 (m,8H), 5.91- 5.87 (m, 0.6H), 5.73-5.71 (m, 0.4H), 5.25-5.1. (m, 0.4H),4.99 (s, 1H), 4.74-4.58 (m, 2H), 4.44-4.15 (m, 1H), 3.87- 3.61 (m, 1H),3.19-3.00 (m, 0.6H), 2.99-2.72 (m, 1.5H), 2.70-2.58 (m, 0.5H), 2.42-2.28(m, 0.5H), 1.97-1.92 (m, 3H), 1.91-1.61 (m, 1H), 1.52-1.15 (m, 3H),1.03-0.92 (m, 0.6H)

Example 2—Preparation of(S)—N-hydroxy-3-phenyl-4-((S)-tetrahydro-2H-pyran-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideand(S)—N-hydroxy-3-phenyl-4-((R)-tetrahydro-2H-pyran-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(S)-3-phenyl-4-((S)-tetrahydro-2H-pyran-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylateand Methyl(S)-3-phenyl-4-((R)-tetrahydro-2H-pyran-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

A solution of oxane-3-carboxylic acid (105 mg, 0.81 mmol, 1.5 equiv) inDMF (3 mL) and DMTMM (300 mg, 1.08 mmol, 2 equiv) were added to an 8-mLvial and the resulting solution was stirred for 30 min at roomtemperature. Methyl(S)-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (150mg, 0.53 mmol, 1 equiv) was then added. The resulting solution wasstirred for 5 h at room temperature and then poured into 30 mL of water.The solution was extracted with EtOAc (3×30 mL). The combined organiclayers were washed with brine (3×30 mL), dried over anhydrous Na₂SO₄,filtered, and concentrated under vacuum. The residue was purified bysilica gel chromatography (EtOAc/pet. ether, 1:10 to 1:1) to afford theracemate of title compounds as a white solid (181 mg, 86% yield). Theracemate was separated by chiral prep-HPLC (Column: Chiralpak IC, 5 μm,2×25 cm; Mobile Phase A: hexanes; Mobile Phase B: EtOH; Flow rate: 16mL/min; Gradient: 50% B for 40 min; Detector: UV 254, 220 nm) to affordthe single isomers of the title compounds as white solids. First elutingisomer, arbitrarily drawn as the S tetrahydropyran isomer: (80 mg, 76%yield); second eluting isomer, arbitrarily drawn as the Rtetrahydropyran isomer: (70 mg, 67% yield). MS: (ES, m/z): 396 [M+H]⁺.

Step-2:(S)—N-Hydroxy-3-phenyl-4-((S)-tetrahydro-2H-pyran-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideand(S)—N-Hydroxy-3-phenyl-4-((R)-tetrahydro-2H-pyran-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into 8-mL vials was added each of the separated isomers from Step 1 (80mg, 0.20 mmol; and 70 mg, 0.18 mmol; 1 equiv) in THF/MeOH (4:1, 2 mL)followed by aq. 1N NaOH (2 equiv) and NH₂OH (50% in H₂O, 120 equiv). Theresulting solution was stirred for 1 h at room temperature. The solidswere removed by filtration and the crude products were purified byprep-HPLC (Column: Xbridge Prep C18 OBD, 5 μm, 19×150 mm; Mobile PhaseA: Water/0.1% formic acid; Mobile Phase B: MeCN; Flow rate: 20 mL/min;Gradient: 5% B to 49% B in 8 min; Detector, UV 254, 220 nm) to affordthe title compounds as white solids. Product from the reaction with thefirst eluting isomer of Step 1: (42.7 mg, 53% yield); ¹H-NMR (400 MHz,DMSO-d₆) δ(ppm): 11.15 (s, 1H), 8.99 (s, 1H), 7.42-7.19 (m, 8H),5.87-5.66 (m, 1H), 5.20-4.56 (m, 4H) 3.91-3.74 (m, 2H), 3.27-3.18 (m,2H), 2.93-2.71 (m, 1H), 1.58-1.03 (m, 4H). MS: (ES, m/z): 397 [M+H]⁺.Product from the reaction with the second eluting isomer of Step 1:(34.6 mg, 49% yield); ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 11.17 (s, 1H),9.02 (s, 1H), 7.44-7.19 (m, 8H), 5.86-5.63 (m, 1H), 5.20-4.58 (m, 4H),3.72-3.58 (m, 1H), 3.45-3.41 (m, 0.5H), 3.28-3.15 (m, 2.5H), 2.82-2.65(m, 1H), 1.99-1.81 (m, 1H), 1.63-1.49 (m, 3H). MS: (ES, m/z): 397[M+H]⁺.

TABLE 2 The following compounds were prepared according to the method ofExample 2. Found Structure M + H ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm)

(ES, m/z): 383 [M + H]⁺ 11.19 (br s, 1H), 9.08 (br s, 1H), 7.46-7.21 (m,8H), 5.90- 5.64 (m, 1H), 5.21-4.58 (m, 4H), 4.09-3.96 (m, 1H), 3.70-3.51(m, 3H), 3.36-3.24 (m, 1H), 1.84-1.59 (m, 2H)

(ES, m/z): 383 [M + H]⁺ 11.19 (br s, 1H), 9.06 (br s, 1H), 7.45-7.22 (m,8H), 5.90- 5.68 (m, 1H), 5.26-4.58 (m, 4H), 3.68-3.60 (m, 2H), 3.49-3.24(m, 3H), 2.26-1.78 (m, 2H)

(ES, m/z): 425 [M + H]⁺ 11.09 (br s, 1H), 9.04 (br s, 1H), 7.45-7.21 (m,8H), 5.90- 5.62 (m, 1H), 5.23-4.57 (m, 4H), 3.19-3.16 (d, J = 11.2 Hz,3H), 3.01-2.99 (m, 1H), 2.68-2.56 (m, 1H), 2.02-1.82 (m, 3H), 1.41-0.93(m, 5H)

(ES, m/z): 425 [M + H]⁺ 11.08 (br s, 1H), 9.06 (br s, 1H), 7.45-7.21 (m,8H), 5.91- 5.62 (m, 1H), 5.24-4.57 (m, 4H), 3.38-3.29 (m, 1H), 3.14-3.13(d, J = 7.2 Hz, 3H), 2.67-2.64 (m, 1H), 1.88- 1.71 (m, 1H), 1.68-1.39(m, 5H), 1.19-0.74 (m, 2H)

Example 3—Preparation of(S)-4-(1-acetylpiperidine-4-carbonyl)-N-hydroxy-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(S)-4-(1-acetylpiperidine-4-carbonyl)-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

1-acetylpiperidine-4-carboxylic acid (49 mg, 0.34 mmol, 1.2 equiv), DMF(3 mL), HATU (129 mg, 0.34 mmol, 1.2 equiv), and DIEA (149 mg, 1.15mmol, 4 equiv) were added to an 8-mL vial. This was followed by thedropwise addition of methyl(S)-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (80mg, 0.28 mmol, 1 equiv) in DMF (2 mL) with stirring at 0° C. and theresulting solution was stirred overnight at room temperature. Thereaction mixture was then poured into 20 mL of H₂O and extracted withEtOAc (3×25 mL). The combined organic layers were washed with brine(2×25 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated undervacuum. The resulting residue was purified by silica gel chromatography(EtOAc/pet. ether, 1:2) to afford the title compound as a yellow oil (33mg, 29% yield). MS: (ES, m/z): 409 [M+H]⁺.

Step-2:(S)-4-(1-Acetylpiperidine-4-carbonyl)-N-hydroxy-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Methyl(S)-4-(1-acetylpiperidine-4-carbonyl)-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(33 mg, 0.08 mmol, 1 equiv), THF/MeOH (4:1, 2 mL), NH₂OH (50% in water,320 mg, 4.84 mmol, 60 equiv), and aq. 1N NaOH (0.16 mL, 2 equiv) wereadded to an 8-mL vial and the resulting solution was stirred for 2 h atroom temperature. The crude product was purified by prep-HPLC(Column:)(Bridge C18 OBD, 5 μm, 19×250 mm; Mobile Phase A: Water/10 mMNH₄HCO₃; Mobile Phase B: MeCN; Gradient: 6% B to 36% B in 8 min;Detector, UV 254, 220 nm) to afford the title compound as an off-whitesolid (7.4 mg, 22% yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 11.18 (brs, 1H), 9.05 (br s, 1H), 7.43-7.20 (m, 8H), 5.91-5.87 (m, 0.6H),5.68-5.58 (m, 0.3H), 5.22 (d, J=16.0 Hz, 0.3H), 4.97-4.88 (m, 1H),4.75-4.58 (m, 2.4H), 2.81-2.65 (m, 1H), 2.59-2.51 (m, 1.6H), 2.41-2.31(m, 0.4H), 2.07 (d, J=16.8 Hz, 3H), 1.94-1.91 (m, 0.6H), 1.85-1.56 (m,3.5H), 1.44-1.37 (m, 1H), 1.12 (d, J=12.8 Hz, 0.4H), 0.89 (d, J=12.8 Hz,0.6H). MS: (ES, m/z): 410 [M+H]⁺.

TABLE 3 The following compounds were prepared according to the method ofExample 3. Found Structure M + H ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm)

(ES, m/z): 383 [M + H]⁺ 11.16 (s, 1H), 9.01 (s, 1H), 7.29-7.42 (m, 3H),7.23 (s, 5H), 6.00-6.06 (t, 1H), 4.98-5.80 (m, 4H), 2.77 (s, 3H),0.76-1.23 (m, 4H)

(ES, m/z): 385 [M + H]⁺ 11.15 (s, 1H), 9.03 (s, 1H), 7.43-7.20 (m, 8H),6.44- 6.40 (m, 0.4H), 5.81-5.77 (m, 0.6H), 5.59-5.54 (m, 0.6H),5.15-5.03 (m, 1H), 4.78-4.41 (m, 2.4H), 2.89 (s, 1H), 2.70 (s, 2H), 1.42(s, 2H), 1.28 (s, 1H), 1.17 (s, 2H), 1.13 (s, 1H)

Example 4—Preparation of(S)—N-hydroxy-3-phenyl-4-pivaloyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(S)-3-phenyl-4-pivaloyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Methyl(S)-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (60mg, 0.21 mmol, 1 equiv), CH₂Cl₂ (5 mL), and Et₃N (107 mg, 1.06 mmol, 5equiv) were added to a 10-mL vial. This was followed by the addition of2,2-dimethylpropanoyl chloride (77 mg, 0.64 mmol, 3 equiv) at 0° C. Theresulting solution was stirred for 2 h at room temperature and thenpoured into 20 mL of water and extracted with CH₂Cl₂ (2×15 mL). Thecombined organic layers were dried over anhydrous Na₂SO₄, filtered, andconcentrated under vacuum to afford the title compound as a yellow solid(78 mg). MS: (ES, m/z): 368 [M+H]⁺.

Step-2:(S)—N-Hydroxy-3-phenyl-4-pivaloyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Methyl(S)-3-phenyl-4-pivaloyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(78 mg, 0.21 mmol, 1 equiv), THF/MeOH (4:1, 2 mL), and NH₂OH (50% inwater, 842 mg, 12.75 mmol, 60 equiv) were added to a 25-mL round-bottomflask. This was followed by the dropwise addition of aq. 1N NaOH (0.4mL, 2 equiv). The resulting solution was stirred for 2 h at roomtemperature. The solids were then removed by filtration and the crudeproduct was purified by prep-HPLC (Column: Xbridge RP C18 OBD, 5 μm,19×150 mm; Mobile Phase A: Water/0.1% formic acid; Mobile Phase B: MeCN;Gradient: 25% B to 50% B in 7 min; Detector, UV 254, 220 nm) to affordthe title compound as a white solid (30.4 mg, 39% yield). ¹H-NMIR (400MHz, DMSO-d₆) δ(ppm): 11.13 (s, 1H), 9.02 (s, 1H), 7.41-7.27 (m, 7H),7.21 (s, 1H), 5.87-5.83 (m, 1H), 5.11-5.07 (m, 1H), 4.71 (s, 2H),4.49-4.43 (m, 1H), 1.13 (s, 9H). MS: (ES, m/z): 369 [M+H]⁺.

TABLE 4 The following compounds were prepared according to the method ofExample 4. Found Structure M + H ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm)

(ES, m/z): 390 [M + H]⁺ 8.55-8.49 (m, 1H), 7.88-7.80 (m, 1H), 7.51-7.41(m, 3H), 7.38-7.20 (m, 6.5H), 6.73-6.71 (m, 0.5H), 6.04-6.00 (m, 0.5H),5.60-5.50 (m, 0.5H), 5.30-5.26 (d, J = 15.6 Hz, 0.5H), 5.05-5.01 (d, J =15.6 Hz, 0. 5H), 4.85-4.81 (m, 1H), 4.78-4.55 (m, 2H)

(ES, m/z): 355 [M + H]⁺ 11.16 (s, 1H), 9.01 (s, 1H), 7.45-7.21 (m, 8H),5.92-5.88 (m, 0.6 H), 5.62-5.58 (m, 0.4H), 5.26-5.22 (m, 0.4H), 4.96 (d,J = 17.6 Hz, 0.6H), 4.88 (d, J = 17.6 Hz, 0.6H), 4.74-4.71 (m, 0.4H),4.68-4.58 (m, 2H), 2.92-2.85 (m, 0.6H), 2.73-2.70 (0.4H), 1.08 (d, J =6.8 Hz, 2H), 0.96 (d, J = 6.4 Hz, 1H), 0.80 (d, J = 6.4 Hz, 1H), 0.68(d, J = 6.8 Hz, 2H)

Example 5—Preparation of(S)—N-hydroxy-4-(4-methyltetrahydro-2H-pyran-4-carbonyl)-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(S)-4-(4-methyltetrahydro-2H-pyran-4-carbonyl)-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into an 8-mL vial was added 4-methyl-tetrahydro-2H-pyran-4-carboxylicacid (50 mg, 0.35 mmol, 1 equiv), and CH₂Cl₂ (4 mL) followed by theaddition of oxalyl chloride (0.35 mL, 4.11 mmol, 2 equiv) and DMF (1drop). The reaction mixture was stirred for 1 h at room temperature. Theresulting solution was then concentrated under vacuum and dissolved inCH₂Cl₂ (1 mL) to provide solution A. Into another 8-mL vial was addedmethyl(S)-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (98mg, 0.35 mmol, 1 equiv) and Et₃N (140 mg, 1.38 mmol, 4 equiv). This wasfollowed by the addition of the solution A at 0° C. and the resultingsolution was stirred overnight at room temperature. The reaction wasthen concentrated under vacuum the resulting residue was purified bysilica gel chromatography (EtOAc/pet. ether, 1:2) to afford the titlecompound as a yellow oil (31 mg, 22% yield). MS: (ES, m/z): 410 [M+H]⁺.

Step-2:(S)—N-Hydroxy-4-(4-methyltetrahydro-2H-pyran-4-carbonyl)-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Methyl(S)-4-(4-methyltetrahydro-2H-pyran-4-carbonyl)-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(31 mg, 0.08 mmol, 1 equiv), THF/MeOH (4:1, 1.6 mL), NH₂OH (50% inwater, 300 mg, 4.54 mmol, 60 equiv), and aq. 1N NaOH (0.15 mL, 2 equiv)were added to an 8-mL vial and the resulting solution was stirred for 2h at room temperature. The crude product was purified by prep-HPLCColumn: Xbridge RP C18 OBD, 5 μm, 19×150 mm; Mobile Phase A: Water/0.1%formic acid; Mobile Phase B: MeCN; Gradient: 20% B to 45% B in 7 min;Detector, UV 254, 220 nm) to afford the title compound as an off-whitesolid (10.1 mg, 33% yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 11.15 (brs, 1H), 9.04 (br s, 1H), 7.40-7.22 (m, 8H), 5.90-5.86 (m, 1H), 5.10 (d,J=16.4 Hz, 1H), 4.75-4.40 (m, 3H), 3.59-3.56 (m, 1H), 3.42-3.37 (m, 1H),3.31-3.21 (m, 1H), 3.19-2.98 (m, 1H), 2.00-1.97 (m, 1H), 1.92-1.70 (m,1H), 1.50-1.31 (m, 2H), 1.24 (s, 3H). MS: (ES, m/z): 410 [M+H]⁺.

TABLE 5 The following compound was prepared according to the method ofExample 5. Found Structure M + H ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm)

(ES, m/z): 425 [M + H]⁺ 11.18 (br s, 1H), 9.03 (br s, 1H), 7.44-7.20 (m,7H), 7.19 (s, 1H), 6.55-6.47 (m, 0.4H), 5.83-5.78 (m, 0.6H), 5.64 (d, J= 16.8 Hz, 0.6H), 5.16-5.01 (m, 1H), 4.84-4.78 (m, 0.4H), 4.61-4.54 (m,1.6H), 4.42-4.32 (m, 0.4H), 2.87 (s, 1H), 2.57 (s, 2H), 2.12-2.07 (m,0.6H), 1.91-1.80 (m, 0.4H), 1.76-1.58 (m, 0.6H), 1.64-1.16 (m, 8.6H)

Example 6—Preparation of(S)—N-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-3-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(S)-3-bromo-4-(((2-hydroxy-1-(4-(trifluoromethyl)phenyl)ethyl)amino)methyl)benzoate

A solution of (S)-2-amino-2-(4-(trifluoromethyl)phenyl)ethan-1-ol (670mg, 3.27 mmol, 1 equiv) in MeCN (60 mL) was added to a 250-mLround-bottom flask. This was followed by the portionwise addition ofK₂CO₃ (2.25 g, 16.28 mmol, 5 equiv). To this mixture was then added asolution of methyl 3-bromo-4-(bromomethyl)benzoate (1000 mg, 3.25 mmol,1 equiv) in MeCN (20 mL) dropwise with stirring and the resultingsolution was stirred overnight at 50° C. in an oil bath. The reactionmixture was then cooled to room temperature and concentrated undervacuum. The resulting residue was dissolved in water (50 mL) andextracted with EtOAc (2×80 mL). The combined organic layers were thendried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum.The resulting residue was purified by silica gel chromatography(EtOAc/pet. ether, 1:1) to afford the title compound as an orange oil(1.04 g, 74% yield). MS: (ES, m/z): 432 [M+H]⁺.

Step-2: Methyl(S)-3-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 20-mL sealed tube was added a solution of methyl(S)-3-bromo-4-(((2-hydroxy-1-(4-(trifluoromethyl)phenyl)ethyl)amino)methyl)benzoate(1.04 g, 2.41 mmol, 1 equiv) in isopropanol (18 mL) followed by theportionwise addition of CuI (230 mg, 1.21 mmol, 0.5 equiv). To thismixture was added K₂CO₃ (500 mg, 3.62 mmol, 1.5 equiv), in portions andthe resulting solution was stirred overnight at 105° C. in an oil bath.The reaction mixture was then cooled to room temperature and the solidswere removed by filtration. The filtrate was concentrated under vacuumand the resulting residue was dissolved in EtOAc (60 mL) and washed withbrine (3×30 mL). The organic layer was dried over anhydrous Na₂SO₄,filtered, and concentrated under vacuum. The resulting residue waspurified by silica gel chromatography (EtOAc/pet. ether, 1:1) to affordthe title compound as a green solid (560 mg, 43% yield). MS: (ES, m/z):352 [M+H]⁺.

Step-3: Methyl(S)-4-(tetrahydro-2H-pyran-4-carbonyl)-3-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into an 8-mL vial was added a solution of oxane-4-carboxylic acid (25mg, 0.19 mmol, 1.12 equiv) in DMF (3 mL) followed by the portionwiseaddition of DMTMM (55.4 mg, 0.2 mmol, 1.2 equiv) at 0° C. The mixturewas then stirred for 1 h at room temperature. To this mixture was addedmethyl(S)-3-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(60 mg, 0.17 mmol, 1 equiv) and the resulting solution was stirredovernight at room temperature. The reaction was diluted with EtOAc (30mL) and washed with brine (3×30 mL). The organic layer was dried overanhydrous Na₂SO₄, filtered, and concentrated under vacuum. The resultingresidue was purified by silica gel chromatography (EtOAc/pet. ether,1:2) to afford the title compound as a light yellow solid (34 mg, 28%yield). MS: (ES, m/z): 464 [M+H]⁺.

Step-4:(S)—N-Hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-3-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

A solution of methyl(S)-4-(tetrahydro-2H-pyran-4-carbonyl)-3-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(34.0 mg, 0.07 mmol, 1 equiv) in THF/MeOH (4:1, 2.5 mL), NH₂OH (50% inwater, 290 mg, 4.39 mmol, 60 equiv), and aq. 1N NaOH (0.15 mL, 2 equiv)were added to an 8-mL vial and the resulting solution was stirred for 3h at room temperature. The crude product was purified by prep-HPLC(Column: Xbridge C18 OBD, 5 μm, 19×150 mm; Mobile Phase A: Water/0.1%formic acid; Mobile Phase B: MeCN; Gradient: 25% B to 50% B in 7 min;Detector, UV 254, 220 nm) to afford the title compound as a white solid(8.1 mg, 24% yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 11.19 (br s, 1H),9.06 (br s, 1H), 7.80-7.74 (m, 2H), 7.63-7.56 (m, 2H), 7.48-7.21 (m,3H), 5.96-5.81 (m, 1H), 5.21 (d, J=16.0 Hz, 0.3H), 5.02 (s, 1.3H),4.80-4.61 (m, 2.4H), 3.87-3.68 (m, 2H), 3.44-3.43 (m, 1H), 3.19-3.17 (m,1H), 2.95-2.93 (m, 0.7H), 2.80-2.73 (m, 0.3H), 1.69-1.57 (m, 2H),1.43-1.40 (m, 1H), 1.13-0.84 (m, 1H). MS: (ES, m/z): 465 [M+H]⁺.

TABLE 6 The following compound was prepared according to the method ofExample 6. Found Structure M + H ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm)

(ES, m/z): 415 [M + H]⁺ 11.12 (s, 1H), 9.08 (s, 1H), 7.48-7.09 (m, 7H),5.90- 5.72 (m, 1H), 4.97 (s, 1H), 4.76-4.57 (m, 3H), 3.86-3.65 (m, 2H),3.44-3.31 (m, 1H), 3.19-3.12 (m, 1H), 2.90- 2.75 (m, 1H), 1.71-1.31 (m,3H), 1.08-0.82 (m, 1H)

Example 7—Preparation of(S)—N-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-3-(p-tolyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(S)-3-bromo-4-(((2-hydroxy-1-(p-tolyl)ethyl)amino)methyl)benzoate

(S)-2-amino-2-(p-tolyl)ethanol (209 mg, 1.380 mmol, 1 equiv), K₂CO₃ (572mg, 4.14 mmol, 3 equiv), and MeCN (15 mL) were added to a 40-mL vialequipped with a stir bar and the resulting slurry was cooled to 0° C. inan ice-water bath. A solution of methyl 3-bromo-4-(bromomethyl)benzoate(425 mg, 1.380 mmol, 1 equiv) in MeCN (3 mL) was then added dropwiseover 10 min while maintaining the internal temperature at 0° C. The icebath was removed and the resulting slurry was allowed to slowly warm toroom temperature. Stirring was continued at room temperature for 16 h.The reaction was concentrated under reduced pressure to remove most ofthe MeCN and the concentrated mixture was partitioned between EtOAc (10mL) and H₂O (5 mL). The phases were separated and the organic phase waswashed with brine (5 mL), dried over Na₂SO₄, filtered, and concentratedto afford the title compound as a pale yellow oil (522 mg). MS: (ES,m/z): 379 [M+H]⁺.

Step-2: Methyl(S)-3-(p-tolyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 40-mL vial equipped with a stir bar was placed methyl(S)-3-bromo-4-(((2-hydroxy-1-(p-tolyl)ethyl)amino)methyl)benzoate (522mg, 1.380 mmol, 1 equiv) in isopropanol (8 mL) and K₂CO₃ (381 mg, 2.76mmol, 2 equiv) followed by the addition of CuI (52.6 mg, 0.276 mmol, 0.2equiv). The resulting solution was heated to reflux for 18 h. Thereaction mixture was then filtered through a celite pad and washed withisopropanol (10 mL). The filtrate was reduced in volume to ˜5 mL and 10NHCl (1.1 equiv) was added dropwise, with stirring, to the filtrate. Theresulting slurry was cooled in an ice bath for 30 min before beingfiltered on a Buchner funnel to afford the HCl salt of the titlecompound as a pale yellow solid (140.4 mg, 30.5% yield). MS: (ES, m/z):298 [M+H]⁺.

Step-3: Methyl(S)-4-(tetrahydro-2H-pyran-4-carbonyl)-3-(p-tolyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Methyl(S)-3-(p-tolyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylatehydrochloride (20 mg, 0.060 mmol, 1 equiv), Et₃N (0.029 mL, 0.210 mmol,3.5 equiv), tetrahydro-2H-pyran-4-carboxylic acid (9.36 mg, 0.072 mmol,1.2 equiv) and dichloroethane (2 mL) were added to a 4-mL vial equippedwith a stir bar. DMC (12.15 mg, 0.072 mmol, 1.2 equiv) was then addedand the resulting solution was stirred at room temperature for 4 h. Thereaction mixture was washed with aq. 1N NaOH (1 mL). The organic layerwas separated, dried over Na₂SO₄, filtered, and concentrated to drynessto afford the title compound as a colorless oil (27.1 mg). MS: (ES,m/z): 410 [M+H]⁺.

Step-4:(S)—N-Hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-3-(p-tolyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Methyl(S)-4-(tetrahydro-2H-pyran-4-carbonyl)-3-(p-tolyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(27.1 mg, 0.066 mmol, 1 equiv), NH₂OH (50% in water, 0.087 mL, 1.32mmol, 20 equiv), and aq. 1N NaOH (0.13 mL, 2 equiv) in a solution ofTHF/MeOH (4:1, 1.5 mL) were added to a 4-mL vial and the resultingsolution was stirred at room temperature overnight. The reaction wasthen concentrated to dryness and purified directly by prep-HPLC (Column:Xbridge Prep C18 OBD, 5 μm, 19×50 mm; Mobile Phase A: Water/0.1% formicacid; Mobile Phase B: MeCN/0.1% formic acid; Gradient: 0% B up to 35% Bin 8 min; Detector, UV 254, 220 nm) to afford the title compound as apale yellow solid (2.7 mg, 9.94% yield). ¹H-NMR (300 MHz, CDCl₃) δ(ppm):7.97-8.12 (m, 1H), 7.05-7.46 (m, 6H), 6.10 (br s, 1H), 5.24-5.61 (m,1H), 4.29-4.85 (m, 3H), 3.79-4.13 (m, 2H), 3.09-3.59 (m, 3H), 2.59-2.85(m, 1H), 2.18-2.46 (m, 3H), 1.55-2.12 (m, 4H), 1.19-1.55 (m, 2H),0.81-1.19 (m, 1H). MS: (ES, m/z): 411 [M+H]⁺.

Example 8—Preparation of(S)-3-(4-chlorophenyl)-N-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(S)-3-bromo-4-(((1-(4-chlorophenyl)-2-hydroxyethyl)amino)methyl)benzoate

(S)-2-amino-2-(4-chlorophenyl)ethan-1-ol (237 mg, 1.38 mmol, 1 equiv),K₂CO₃ (572 mg, 4.14 mmol, 3 equiv), and MeCN (15 mL) were added to a40-mL vial equipped with a stir bar and the resulting slurry was cooledto 0° C. in an ice-water bath. A solution of methyl3-bromo-4-(bromomethyl)benzoate (425 mg, 1.38 mmol, 1 equiv) in MeCN (3mL) was then added dropwise over 10 min while maintaining the internaltemperature at 0° C. The ice bath was removed and the resulting slurrywas allowed to slowly warm to room temperature. Stirring was continuedat room temperature for 16 h. The reaction was concentrated underreduced pressure to remove most of the MeCN and the concentrated mixturewas partitioned between EtOAc (10 mL) and H₂O (5 mL). The phases wereseparated and the organic phase was washed with brine (5 mL), dried overNa₂SO₄, filtered, and concentrated to afford the title compound as apale yellow oil (572 mg). MS: (ES, m/z): 399 [M+H]⁺.

Step-2: Methyl(S)-3-(4-chlorophenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 40-mL vial equipped with a stir bar was placed methyl(S)-3-bromo-4-(((1-(4-chlorophenyl)-2-hydroxyethyl)amino)methyl)benzoate(572 mg, 1.435 mmol, 1 equiv) in isopropanol (5 mL) and K₂CO₃ (397 mg,2.87 mmol, 2 equiv) followed by the addition of CuI (54.6 mg, 0.287mmol, 0.2 equiv). The resulting solution was heated to reflux for 18 h.A second portion of K₂CO₃ (397 mg, 2.87 mmol, 2 equiv) was addedfollowed by the addition of a second portion of copper (I) iodide (54.6mg, 0.287 mmol, 0.2 equiv). The resulting solution was then heated toreflux for 18 h. The resulting mixture was filtered through a celite padand washed with isopropanol (10 mL). The filtrate was reduced in volumeto ˜5 mL and 10N HCl (1.1 equiv) was added dropwise, with stirring, tothe filtrate. The resulting slurry was cooled in an ice bath for 30 minbefore being filtered on a Buchner funnel to afford the HCl salt of thetitle compound as a pale yellow solid (110 mg, 21.7% yield). MS: (ES,m/z): 318 [M+H]⁺.

Step-3: Methyl(S)-3-(4-chlorophenyl)-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Methyl(S)-3-(4-chlorophenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylatehydrochloride (20 mg, 0.056 mmol, 1 equiv), Et₃N (0.024 mL, 0.169 mmol,3.5 equiv), tetrahydro-2H-pyran-4-carboxylic acid (8.82 mg, 0.068 mmol,1.2 equiv), and dichloroethane (2 mL) were added to a 4-mL vial equippedwith a stir bar. DMC (11.45 mg, 0.068 mmol, 1.2 equiv) was then addedand the resulting solution was stirred at room temperature for 4 h. Thereaction mixture was washed with aq. 1N NaOH (1 mL). The organic layerwas separated, dried over Na₂SO₄, filtered, and concentrated to drynessto afford the title compound as a colorless oil. MS: (ES, m/z): 430[M+H]⁺.

Step-4:(S)-3-(4-Chlorophenyl)-N-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Methyl(S)-3-(4-chlorophenyl)-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(24.07 mg, 0.056 mmol, 1 equiv), NH₂OH (50% in water, 0.074 ml, 1.12mmol, 20 equiv), and aq. 1N NaOH (0.11 mL, 2 equiv) in a solution ofTHF/MeOH (4:1, 1.5 mL) were added to a 4-mL vial and the resultingsolution was stirred at room temperature overnight. The reaction wasconcentrated to dryness and purified directly by prep-HPLC (Column:Xbridge Prep C18 OBD, 5 μm, 19×50 mm; Mobile Phase A: Water/0.1% formicacid; Mobile Phase B: MeCN/0.1% formic acid; Flow rate: 23 mL/min;Gradient: 15% B up to 65% B in 8 min; Detector, UV 254, 220 nm) toafford the title compound as a pale yellow solid (5.8 mg, 24% yield).MS: (ES, m/z): 431 [M+H]⁺.

Example 9—Preparation of(S)-3-(3-chlorophenyl)-N-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(S)-3-bromo-4-(((1-(3-chlorophenyl)-2-hydroxyethyl)amino)methyl)benzoate

(S)-2-amino-2-(3-chlorophenyl)ethan-1-ol (250 mg, 1.20 mmol, 1 equiv),K₂CO₃ (664 mg, 4.81 mmol, 4 equiv) and MeCN (15 mL) were added to a40-mL vial equipped with a stir bar and the resulting slurry was cooledto 0° C. in an ice-water bath. A solution of methyl3-bromo-4-(bromomethyl)benzoate (370 mg, 1.20 mmol, 1 equiv) in MeCN (3mL) was then added dropwise over 10 min while maintaining the internaltemperature at 0° C. The ice bath was removed and the resulting slurrywas allowed to slowly warm to room temperature. Stirring was continuedat room temperature for 16 h. The resulting mixture was concentratedunder reduced pressure to remove most of the MeCN and the concentratedmixture was partitioned between EtOAc (10 mL) and H₂O (5 mL). The phaseswere separated and the organic phase was washed with brine (5 mL), driedover Na₂SO₄, filtered, and concentrated to afford the title compound asa pale yellow oil (436 mg). MS: (ES, m/z): 399 [M+H]⁺.

Step-2: Methyl(S)-3-(3-chlorophenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 40-mL vial equipped with a stir bar was added methyl(S)-3-bromo-4-(((1-(3-chlorophenyl)-2-hydroxyethyl)amino)methyl)benzoate(436 mg, 1.09 mmol, 1 equiv) in isopropanol (5 mL) and K₂CO₃ (302 mg,2.19 mmol, 2 equiv) followed by CuI (41.7 mg, 0.219 mmol, 0.2 equiv).The resulting solution was heated to reflux for 18 h. The mixture wasthen filtered through a celite pad and washed with isopropanol (10 mL).The filtrate was reduced in volume to ˜5 mL and 10N HCl (1.1 equiv) wasadded dropwise, with stirring, to the filtrate. The resulting slurry wascooled in an ice bath for 30 min before being filtered on a Buchnerfunnel to afford the HCl salt of the title compound as a pale yellowsolid (75.6 mg, 19.5% yield). MS: (ES, m/z): 318 [M+H]⁺.

Step-3: Methyl(S)-3-(3-chlorophenyl)-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Methyl(S)-3-(3-chlorophenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylatehydrochloride (22 mg, 0.062 mmol, 1 equiv), Et₃N (0.026 mL, 0.186 mmol,3 equiv), tetrahydro-2H-pyran-4-carboxylic acid (9.70 mg, 0.075 mmol,1.2 equiv), and dichloroethane (2 mL) were added to a 4-mL vial equippedwith a stir bar. DMC (12.6 mg, 0.075 mmol, 1.2 equiv) was then added andthe resulting solution was stirred at 50° C. for 16 h. The reactionmixture was washed with aq. 1N NaOH (1 mL). The organic layer wasseparated, dried over Na₂SO₄, filtered, and concentrated to dryness toafford the title compound as a pale yellow oil. MS: (ES, m/z): 430[M+H]⁺.

Step-4:(S)-3-(3-Chlorophenyl)-N-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Methyl(S)-3-(3-chlorophenyl)-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(26.7 mg, 0.062 mmol, 1 equiv), NH₂OH (50% in water, 0.082 mL, 1.24mmol, 20 equiv), and aq. 1N NaOH (0.12 mL, 2 equiv) in a solution ofTHF/MeOH (4:1, 1.5 mL) were added to a 4-mL vial and the resultingsolution was stirred at room temperature overnight. The reaction wasconcentrated to dryness and purified directly by prep-HPLC (Column:Xbridge Prep C18 OBD, 5 μm, 19×50 mm; Mobile Phase A: Water/0.1% formicacid; Mobile Phase B: MeCN/0.1% formic acid; Flow rate: 23 mL/min;Gradient: 15% B up to 65% B in 8 min; Detector, UV 254, 220 nm) toafford the title compound as a pale yellow solid (5.3 mg, 20% yield).¹H-NMR (300 MHz, CDCl₃) δ(ppm): 7.94 (br s, 1H), 6.92-7.52 (m, 6H), 6.04(br s, 1H), 4.99-5.55 (m, 1H), 4.17-4.78 (m, 3H), 3.63-4.07 (m, 2H),3.05-3.49 (m, 2H), 2.44-2.76 (m, 1H), 0.90-2.05 (m, 7H). MS: (ES, m/z):431 [M+H]⁺.

Example 10—Preparation of(S)-3-(4-fluorophenyl)-N-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(S)-3-bromo-4-(((1-(4-fluorophenyl)-2-hydroxyethyl)amino)methyl)benzoate

(S)-2-amino-2-(4-fluorophenyl)ethan-1-ol (260 mg, 1.68 mmol, 1 equiv),K₂CO₃ (572 mg, 4.14 mmol, 3 equiv), and MeCN (15 mL) were added to a40-mL vial equipped with a stir bar and the resulting slurry was cooledto 0° C. in an ice-water bath. A solution of methyl3-bromo-4-(bromomethyl)benzoate (425 mg, 1.38 mmol, 1 equiv) in MeCN (3mL) was then added dropwise over 10 min while maintaining the internaltemperature at 0° C. The ice bath was removed and the resulting slurrywas allowed to slowly warm to room temperature. Stirring was continuedat room temperature for 16 h. The reaction was concentrated underreduced pressure to remove most of the MeCN and the concentrated mixturewas partitioned between EtOAc (10 mL) and H₂O (5 mL). The phases wereseparated and the organic phase was washed with brine (5 mL), dried overNa₂SO₄, filtered, and concentrated to afford the title compound as apale yellow oil (592 mg). MS: (ES, m/z): 383 [M+H]⁺.

Step-2: Methyl(S)-3-(4-fluorophenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 40-mL vial equipped with a stir bar was added methyl(S)-3-bromo-4-(((1-(4-fluorophenyl)-2-hydroxyethyl)amino)methyl)benzoate(592 mg, 1.55 mmol, 1 equiv) in isopropanol (5 mL) and K₂CO₃ (642 mg,4.65 mmol, 2 equiv) followed by CuI (59 mg, 0.31 mmol, 0.2 equiv). Theresulting solution was heated to reflux for 18 h. The resulting mixturewas filtered through a celite pad and washed with isopropanol (10 mL).The filtrate was reduced in volume to ˜5 mL and 10N HCl (1.1 equiv) wasadded dropwise, with stirring, to the filtrate. The resulting slurry wascooled in an ice bath for 30 min before being filtered on a Buchnerfunnel to afford the HCl salt of the title compound as a pale yellowsolid (119.6 mg, 22.9% yield). MS: (ES, m/z): 302 [M+H]⁺.

Step-3: Methyl(S)-3-(4-fluorophenyl)-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Methyl(S)-3-(4-fluorophenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylatehydrochloride (60 mg, 0.178 mmol, 1 equiv), Et₃N (0.087 mL, 0.622 mmol,3.5 equiv), tetrahydro-2H-pyran-4-carboxylic acid (27.7 mg, 0.213 mmol,1.2 equiv), and dichloroethane (2 mL) were added to a 4-mL vial equippedwith a stir bar. DMC (36.0 mg, 0.213 mmol, 1.2 equiv) was then added andthe resulting solution was stirred at room temperature for 4 h. Thereaction mixture was washed with aq. 1N NaOH (1 mL) and the organiclayer was separated, dried over Na₂SO₄, filtered, and concentrated todryness to afford the title compound as a colorless oil (86.6 mg). MS:(ES, m/z): 414 [M+H]⁺.

Step-4:(S)-3-(4-Fluorophenyl)-N-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Methyl(S)-3-(4-fluorophenyl)-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(86.8 mg, 0.21 mmol, 1 equiv), NH₂OH (50% in water, 0.074 mL, 6.32 mmol,20 equiv), and aq. 1N NaOH (0.63 mL, 2 equiv) in a solution of THF/MeOH(4:1, 2.5 mL) were added to a 4-mL vial equipped with a stir bar and theresulting solution was stirred at room temperature overnight. Thereaction was then concentrated to dryness and purified directly byprep-HPLC (Column: Xbridge Prep C18 OBD, 5 μm, 19×50 mm; Mobile Phase A:Water/0.1% formic acid; Mobile Phase B: MeCN/0.1% formic acid; Flowrate: 23 mL/min; Gradient: 0% B up to 35% B in 8 min; Detector, UV 254,220 nm) to afford the title compound as a pale yellow solid (43.9 mg,33.5% yield). ¹H-NMR (300 MHz, CDCl₃) δ(ppm): 8.41-8.79 (m, 1H),7.83-8.24 (m, 1H), 7.33-7.61 (m, 1H), 7.09-7.23 (m, 3H), 6.90-7.09 (m,2H), 6.84 (br s, 1H), 5.94 (br d, J=7.6 Hz, 1H), 5.37 (br s, 1H), 5.21(br d, J=14.1 Hz, 1H), 4.59 (br d, J=18.2 Hz, 1H), 4.46 (br s, 1H), 4.30(br d, J=14.1 Hz, 1H), 3.91 (br d, J=10.3 Hz, 1H), 3.77 (br s, 1H),3.08-3.44 (m, 2H), 2.52-2.89 (m, 1H), 1.80 (br s, 1H), 1.48-1.72 (m,2H), 1.33 (br s, 1H). MS: (ES, m/z): 415 [M+H]⁺.

Example 11—Preparation of(S)—N-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-3-(o-tolyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(S)-3-bromo-4-(((2-hydroxy-1-(o-tolyl)ethyl)amino)methyl)benzoate

(S)-2-amino-2-(o-tolyl)ethan-1-ol (500 mg, 3.31 mmol, 2.34 equiv), K₂CO₃(572 mg, 4.14 mmol, 3 equiv), and MeCN (15 mL) were added to a 40-mLvial equipped with a stir bar and the resulting slurry was cooled to 0°C. in an ice-water bath. A solution of methyl3-bromo-4-(bromomethyl)benzoate (425 mg, 1.38 mmol, 1 equiv) in MeCN (3mL) was then added dropwise over 10 min while maintaining the internaltemperature at 0° C. The ice bath was removed and the resulting slurrywas allowed to slowly warm to room temperature. Stirring was continuedat room temperature for 16 h. The reaction mixture was concentratedunder reduced pressure to remove most of the MeCN and the concentratedmixture was partitioned between EtOAc (10 mL) and H₂O (5 mL). The phaseswere separated and the organic phase was washed with brine (5 mL), driedover Na₂SO₄, filtered, and concentrated to afford the title compound asa yellow oil (725.7 mg). MS: (ES, m/z): 379 [M+H]⁺.

Step-2: Methyl(S)-3-(o-tolyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 40-mL vial equipped with a stir bar was placed methyl(S)-3-bromo-4-(((2-hydroxy-1-(o-tolyl)ethyl)amino)methyl)benzoate (725.7mg, 1.92 mmol, 1 equiv) in isopropanol (10 mL) and K₂CO₃ (795 mg, 5.76mmol, 2 equiv) was added followed by CuI (73.1 mg, 0.384 mmol, 0.2equiv). The resulting solution was heated to reflux for 18 h. Theresulting mixture was filtered through a celite pad and washed withisopropanol (10 mL). The filtrate was reduced in volume to ˜3 mL and 10NHCl (1.1 equiv) was added dropwise, with stirring, to the filtrate. Theresulting slurry was cooled in an ice bath for 30 min before beingfiltered on a Buchner funnel to afford the HCl salt of the titlecompound as a brown oil (772.6 mg). MS: (ES, m/z): 326 [M+H]⁺.

Step-3: Methyl(S)-4-(tetrahydro-2H-pyran-4-carbonyl)-3-(o-tolyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Methyl(S)-3-(o-tolyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylatehydrochloride (250 mg, 0.691 mmol, 1 equiv), Et₃N (0.385 mL, 2.76 mmol,4 equiv), tetrahydro-2H-pyran-4-carboxylic acid (27.7 mg, 0.213 mmol,1.5 equiv), and CH₂Cl₂ (7 mL) were added to a 4-mL vial equipped with astir bar. DMC (175 mg, 1.036 mmol, 1.2 equiv) was then added and theresulting solution was stirred at room temperature for 5 h. The reactionmixture was washed with aq. 1N NaOH (1 mL) and the organic layer wasseparated, dried over Na₂SO₄, filtered, and concentrated. The crudeproduct was then purified by prep-HPLC (Column: Xbridge Prep C18 OBD, 5μm, 19×50 mm; Mobile Phase A: Water/0.1% formic acid; Mobile Phase B:MeCN/0.1% formic acid; Flow rate: 23 mL/min; Gradient: 35% B up to 85% Bin 8 min; Detector, UV 254, 220 nm) to afford the title compound as ayellow oil (55.7 mg, 18.4% yield). MS: (ES, m/z): 438 [M+H]⁺.

Step-4:(S)—N-Hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-3-(o-tolyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Methyl(S)-4-(tetrahydro-2H-pyran-4-carbonyl)-3-(o-tolyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(55.7 mg, 0.127 mmol, 1 equiv), NH₂OH (50% in water, 0.168 mL, 2.55mmol, 20 equiv), and aq. 1N NaOH (0.26 mL, 2 equiv) in a solution ofTHF/MeOH (4:1, 2 mL) were added to a 4-mL vial and the resultingsolution was stirred at room temperature overnight. The reaction wasconcentrated to dryness and purified directly by prep-HPLC (Column:Xbridge Prep C18 OBD, 5 μm, 19×50 mm; Mobile Phase A: Water/0.1% formicacid; Mobile Phase B: MeCN/0.1% formic acid; Flow rate: 23 mL/min;Gradient: 15% B up to 65% B in 8 min; Detector, UV 254, 220 nm) toafford the title compound as an off-white solid (5.1 mg, 9.76% yield).MS: (ES, m/z): 411 [M+H]⁺.

Example 12—Preparation of(R)—N-hydroxy-3-(pyridin-3-yl)-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideand(S)—N-hydroxy-3-(pyridin-3-yl)-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl3-bromo-4-(((2-hydroxy-1-(pyridin-3-yl)ethyl)amino)methyl)benzoate

2-Amino-2-(pyridin-3-yl)ethan-1-ol dihydrochloride (980 mg, 4.64 mmol, 2equiv) in MeCN (40 mL) was added to a 250-mL round-bottom flask followedby the portionwise addition of K₂CO₃ (1.29 g, 9.33 mmol, 4 equiv). Tothis mixture was then added a solution of methyl3-bromo-4-(bromomethyl)benzoate (713 mg, 2.32 mmol, 1 equiv) in MeCN (20mL) dropwise with stirring and the resulting solution was stirredovernight at room temperature. The mixture was then concentrated undervacuum and the resulting residue was dissolved in 40 mL of water andextracted with EtOAc (3×60 mL). The combined organic layers were driedover anhydrous Na₂SO₄, filtered, and concentrated under vacuum. Theresidue was purified by silica gel chromatography (MeOH/CH₂Cl₂, 1:20) toafford the title compound as a light brown solid (380 mg, 43% yield).MS: (ES, m/z): 365 [M+H]⁺.

Step-2: Methyl3-(pyridin-3-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

A solution of methyl3-bromo-4-((2-hydroxy-1-(pyridin-3-yl)ethylamino)methyl)benzoate (260mg, 0.71 mmol, 1 equiv) in isopropanol (8 mL) was added to a 10-mLsealed tube purged and maintained with an inert atmosphere of nitrogenfollowed by the portionwise addition of K₂CO₃ (147.5 mg, 1.07 mmol, 1.5equiv). To this mixture was added CuI (67.6 mg, 0.35 mmol, 0.5 equiv) inportions and the resulting solution was stirred overnight at 105° C. inan oil bath. The reaction mixture was then cooled to room temperaturewith a water/ice bath and concentrated under vacuum. The residue wasdissolved in EtOAc (80 mL) and washed with brine (3×30 mL). The organiclayer was then dried over anhydrous Na₂SO₄, filtered, and concentratedunder vacuum to afford the title compound as light yellow oil (210 mg)which was used to the next step without purification. MS: (ES, m/z): 285[M+H]⁺.

Step-3: Methyl(R)-3-(pyridin-3-yl)-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylateand Methyl(S)-3-(pyridin-3-yl)-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

A solution of oxane-4-carboxylic acid (205 mg, 1.58 mmol, 5 equiv) inDMF (2.5 mL) was added to an 8-mL vial. This was followed by theportionwise addition of DMTMM (438 mg, 1.58 mmol, 5 equiv) at 0° C. Themixture was then stirred for 2 h at room temperature. To this mixturewas added methyl3-(pyridin-3-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(90 mg, 0.32 mmol, 1 equiv) and the resulting solution was stirredovernight at room temperature. The reaction mixture was purified byflash-prep-HPLC (Column: C18 silica gel, 40 g, 20-45 μm, 100 Å; MobilePhase A: Water/0.05% TFA; Mobile Phase B: MeCN; Flow rate: 80 mL/min;Gradient: 5% B to 30% B in 20 min; Detector: UV 254, 220 nm). Thecollected fractions were concentrated under vacuum to remove MeCN andthe pH value of the solution was adjusted to 8 with aq. 2N NaOH. Theresulting solution was then extracted with CH₂Cl₂ (2×200 mL), dried overanhydrous Na₂SO₄, filtered, and concentrated under vacuum to afford theracemate of the title compounds as a white solid (75 mg, 61% yield). Theracemate was separated by chiral Prep-HPLC (Column: Chiralpak IC, 5 μm,2×25 cm; Mobile Phase: MeOH; Flow rate: 15 mL/min; Detector: UV 254, 220nm) to afford the single isomers of the title compounds as white solids.First eluting isomer, arbitrarily drawn as the R isomer: (23 mg, 30%yield); second eluting isomer, arbitrarily drawn as the S isomer: (25mg, 32% yield). MS: (ES, m/z): 397 [M+H]⁺.

Step-4:(R)—N-hydroxy-3-(pyridin-3-yl)-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideand(S)—N-hydroxy-3-(pyridin-3-yl)-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into 8-mL vials was added each of the separated isomers from Step 3 (23mg, 0.06 mmol; and 25 mg, 0.06 mmol; 1 equiv) in THF/MeOH (4:1, 2.5 mL),followed by aq. 1N NaOH (2 equiv) and NH₂OH (50% in H₂O, 60 equiv). Theresulting solution was stirred for 3 h at room temperature and the crudeproducts were purified by prep-HPLC (Column: Xbridge C18 OBD, 5 μm,19×250 mm; Mobile Phase A: Water/10 mM NH₄HCO₃; Mobile Phase B: MeCN;Gradient: 5% B to 40% B in 8 min; Detector, UV 254, 220 nm) to affordthe title compounds as white solids. Product from the reaction with thefirst eluting isomer of Step 3: (14.5 mg, 63% yield); ¹H-NMR (400 MHz,DMSO-d₆) δ(ppm): 11.17 (br s, 1H), 9.04 (br s, 1H), 8.65-8.51 (m, 2H),7.77-7.73 (m, 1H), 7.46-7.22 (m, 4H), 5.92-5.76 (m, 1H), 5.19-4.60 (m,4H), 3.84-3.68 (m, 2H), 3.49-3.32 (m, 1H), 3.19-3.16 (m, 1H), 2.93 (br,1H), 1.67-1.50 (m, 2H), 1.49-1.35 (m, 1H), 1.13-0.86 (m, 1H). Productfrom the reaction with the second eluting isomer of Step 3: (13 mg, 52%yield); ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 11.17 (br s, 1H), 9.04 (br s,1H), 8.65-8.51 (m, 2H), 7.77-7.76 (m, 1H), 7.46-7.22 (m, 4H), 5.92-5.88(m, 1H), 5.19-4.60 (m, 4H), 3.84-3.67 (m, 2H), 3.42-3.32 (m, 1H),3.19-3.16 (m, 1H), 2.93 (br, 1H), 1.67-1.50 (m, 2H), 1.49-1.32 (m, 1H),1.13-0.87 (m, 1H). MS: (ES, m/z): 398 [M+H]⁺.

TABLE 7 The following compounds were prepared according to the method ofExample 12. Found Structure M + H ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm)

(ES, m/z): 415 [M + H]⁺ 11.17 (s, 1H), 9.05 (s, 1H), 7.50-7.21 (m, 7H),5.99-5.76 (m, 1H), 5.26-5.21 (d, J = 17.2 Hz, 1H), 5.09-5.05 (d, J =17.6 Hz, 1H), 4.82-4.75 (m, 1H), 4.47-4.42 (m, 1H), 3.87-3.69 (m, 2H),3.47-3.41 (m, 1H), 3.25-3.18 (m, 1H), 2.97-2.78 (m, 1H), 1.73-1.1.36 (m,3H), 1.04-0.90 (m, 1H)

(ES, m/z): 415 [M + H]⁺ 11.18 (s, 1H), 9.05 (s, 1H), 7.50-7.21 (m, 7H),5.90-5.76 (m, 1H), 5.26-5.21 (d, J = 17.2 Hz, 1H), 5.10-5.05 (d, J = 18Hz, 1H), 4.82-4.75 (m, 1H), 4.47-4.43 (m, 1H), 3.87- 3.69 (m, 2H),3.47-3.41 (m, 1H), 3.25-3.19 (m, 1H), 2.97-2.78 (m, 1H), 1.73-1.36 (m,3H), 1.04-0.90 (m, 1H)

Example 13—Preparation of(S)—N-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-3-(2-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideand(R)—N-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-3-(2-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl3-bromo-4-(((2-hydroxy-1-(2-(trifluoromethyl)phenyl)ethyl)amino)methyl)benzoate

A solution of 2-amino-2-(2-(trifluoromethyl)phenyl)ethan-1-ol (2 g, 9.75mmol, 2 equiv) in MeCN (40 mL) and K₂CO₃ (4 g, 28.94 mmol, 3 equiv) wereadded to a 250-mL round-bottom flask. To this mixture was added asolution of methyl 3-bromo-4-(bromomethyl)benzoate (3 g, 9.74 mmol, 1equiv) in MeCN (40 mL) dropwise with stirring and the resulting solutionwas stirred overnight at 50° C. in an oil bath. The solids were removedby filtration and the filtrate was concentrated under vacuum and theresulting residue was purified by silica gel chromatography (EtOAc/pet.ether, 1:3) to afford the title compound as a yellow solid (4.14 g, 98%yield). MS: (ES, m/z): 432 [M+H]⁺.

Step-2: Methyl3-(2-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 150-mL pressure tank reactor purged and maintained with an inertatmosphere of nitrogen was added a solution of methyl3-bromo-4-(((2-hydroxy-1-(2-(trifluoromethyl)phenyl)ethyl)amino)methyl)benzoate(4.14 g, 9.58 mmol, 1 equiv) in isopropanol (130 mL), K₂CO₃ (1.99 g,14.40 mmol, 1.5 equiv), and CuI (910 mg, 4.78 mmol, 0.5 equiv) and theresulting solution was stirred for 18 h at 110° C. in an oil bath. Thereaction mixture was then cooled to room temperature. The solids wereremoved by filtration and the filtrate was concentrated under vacuum.The residue was dissolved in CH₂Cl₂ (50 mL) and washed with brine (2×30mL). The organic phase was dried over anhydrous MgSO₄, filtered, andconcentrated under vacuum. The resulting residue was purified byflash-prep-HPLC (Column: C18 silica gel; Mobile Phase A: Water/0.05%TFA; Mobile Phase B: MeCN; Gradient: 25% B to 30% B in 20 min; Detector:UV 254 nm) to afford the title compound as a yellow solid (1.13 g, 34%yield). MS: (ES, m/z): 352 [M+H]⁺.

Step-3: Methyl(R)-4-(tetrahydro-2H-pyran-4-carbonyl)-3-(2-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylateand Methyl(R)-4-(tetrahydro-2H-pyran-4-carbonyl)-3-(2-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

A solution of oxane-4-carboxylic acid (167 mg, 1.28 mmol, 3 equiv) inDMF (8 mL) was added to a 50-mL round-bottom flask. This was followed bythe addition of DMTMM (355 mg, 1.28 mmol, 3 equiv) and the resultingmixture was stirred for 3 h at room temperature. To this mixture wasadded methyl3-(2-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(150 mg, 0.43 mmol, 1 equiv) and the resulting solution was stirred for16 h at room temperature. The solution was then diluted with H₂O (30 mL)and extracted with EtOAc (4×30 mL). The combined organic layers werewashed with brine (2×30 mL), dried over anhydrous Na₂SO₄, filtered, andconcentrated under vacuum. The crude product was purified byflash-prep-HPLC (Column: C18 silica gel, 40 g; Mobile Phase A:Water/0.05% TFA; Mobile Phase B: MeCN; Gradient: 5% B to 30% B in 15min; Detector: UV 254 nm). The collected fractions were concentratedunder vacuum to remove MeCN and the resulting solution was extractedwith CH₂Cl₂ (3×30 mL), dried over anhydrous Na₂SO₄, filtered, andconcentrated under vacuum to afford the racemate of the title compoundsas a white solid (130 mg, 59% yield). The racemate was separated bychiral prep-HPLC (Column: Chiralpak IC, 5 μm, 2×25 cm; Mobile Phase A:hexanes/CH₂Cl₂ (3:1), Mobile Phase B: EtOH; Flow rate: 20 mL/min;Detector: UV 254, 220 nm) to afford the single isomers of the titlecompounds as colorless oils. First eluting isomer, arbitrarily drawn asthe S isomer: (54 mg, 41% yield); second eluting isomer, arbitrarilydrawn as the R isomer: (44 mg, 35% yield). MS: (ES, m/z): 464 [M+H]⁺.

Step-4:(S)—N-Hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-3-(2-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideand(R)—N-Hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-3-(2-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into 8-mL vials was added each of the separated isomers from Step 3 (54mg, 0.12 mmol; and 44 mg, 0.09 mmol; 1 equiv) in THF/MeOH (4:1, 3 mL)followed by aq. 1N NaOH (2 equiv) and NH₂OH (50% in H₂O, 60 equiv). Theresulting solution was stirred for 2 h at room temperature and the crudeproducts were purified by prep-HPLC (Column: Xbridge C18 OBD, 5 μm,19×150 mm; Mobile Phase A: Water/0.1% formic acid; Mobile Phase B: MeCN;Gradient: 25% B to 55% B in 7 min; Detector, UV 254, 220 nm) to affordthe title compounds as white solids. Product from the reaction with thefirst eluting isomer of Step 3: (19.4 mg, 36% yield); ¹H-NMR (400 MHz,DMSO-d₆) δ(ppm): 11.14 (br s, 1H), 9.04 (br s, 1H), 7.78-7.32 (m, 6H),7.22-7.20 (m, 1H), 5.91-5.87 (m, 1H), 5.61-5.47 (m, 1H), 5.25-5.17 (m,1H), 5.12-4.91 (m, 1H), 4.38-4.24 (m, 1H), 3.83-3.60 (m, 2H), 3.48-3.42(m, 1H), 3.32-3.12 (m, 1H), 2.97-2.85 (m, 1H), 1.65-1.61 (m, 1H),1.50-1.38 (m, 2H), 1.06-1.03 (m, 1H). Product from the reaction with thesecond eluting isomer of Step 3: (19.1 mg, 43% yield); ¹H-NMR (400 MHz,DMSO-d₆) δ(ppm): 11.16 (br s, 1H), 9.04 (br s, 1H), 7.87-7.32 (m, 6H),7.22-7.20 (m, 1H), 5.91-5.87 (m, 1H), 5.61-5.47 (m, 1H), 5.28-5.12 (m,1H), 4.97-4.91 (m, 1H), 4.38-4.24 (m, 1H), 3.83-3.60 (m, 2H), 3.48-3.42(m, 1H), 3.32-3.14 (m, 1H), 3.00-2.84 (m, 1H), 1.65-1.37 (m, 3H),1.06-1.03 (m, 1H). MS: (ES, m/z): 465 [M+H]⁺.

TABLE 8 The following compounds were prepared according to the method ofExample 13. Found Structure M + H ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm)

(ES, m/z): 465 [M + H]⁺ 11.16 (s, 1H), 9.01 (s, 1H), 7.71-7.61 (m, 4H),7.46- 7.20 (m, 3H), 5.96-5.83 (m, 1H), 5.23-5.02 (m, 2H), 4.83-4.60 (m,2H), 3.86-3.66 (m, 2H), 3.45-3.11 (m, 2H), 2.92-2.70 (m, 1H), 1.66-1.38(m, 3H), 1.09-0.85 (m, 1H)

(ES, m/z): 465 [M + H]⁺ 11.16 (s, 1H), 9.01 (s, 1H), 7.71-7.61 (m, 4H),7.46- 7.20 (m, 3H), 5.96-5.83 (m, 1H), 5.23-5.02 (m, 2H), 4.83-4.60 (m,2H), 3.86-3.66 (m, 2H), 3.45-3.41 (m, 1H), 3.20-3.11 (m, 1H), 2.92-2.70(m, 1H), 1.66-1.38 (m, 3H), 1.09-0.85 (m, 1H)

Example 14—Preparation of(S)-4-acetyl-N-hydroxy-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(S)-4-acetyl-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

A 2-mL reaction vial was charged with methyl(S)-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(0.2M in 1,2-dichloroethane, 150 μL, 30 μmol) and acetic acid (0.2M inDMA/10% Et₃N, 165 μL, 33 μmol). A solution of DMC (0.2M in1,2-dichloroethane, 165 μL, 33 μmol) was then added and the vial wassealed and shaken at room temperature overnight. The reaction mixturewas diluted with brine (500 μL) and extracted with EtOAc (2×600 μL). Thecombined organic layers were evaporated to dryness under reducedpressure and taken to the next step without further purification.

Step-2:(S)-4-Acetyl-N-hydroxy-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

THF/MeOH (3:1, 180 μL) was added to a vial containing methyl(S)-4-acetyl-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylateand the resulting solution was shaken at 50° C. for 15 min to dissolvethe residue. NH₂OH (50% in water, 125 μL) was then added, followed byaq. 1N NaOH (85 μL) and the vial was sealed and shaken at roomtemperature overnight. The solvent was evaporated under reduce pressureand the resulting residue was dissolved in DMSO (500 μL) and purified byHPLC to afford the title compound. MS: (ES, m/z): 327 [M+H]⁺.

TABLE 9 The following compounds were prepared according to the method ofExample 14. Found M + H Structure (ES)

407

397

383

Example 15—In Vitro Histone Deacetylase Assay

The enzymatic HDAC6 assay was performed using electrophoretic mobilityshift assay. Full length human recombinant HDAC6 protein was expressedin baculoviral system and purified by affinity chromatography. Theenzymatic reactions were assembled in 384-well plates in a total volumeof 25 μL of a reaction buffer comprising: 100 mM HEPES, pH 7.5, 25 mMKCl, 0.1% bovine serum albumin, 0.01% Triton X-100, 1% DMSO (fromcompounds), 2 μM of the fluorescently labeled peptide substrate, andenzyme. The enzyme was added at a final concentration of 1 nM. Thepeptide substrate RHKK(Ac)-NH₂ was used. The compounds were tested at 12concentrations spaced by 3x dilution intervals. Negative control samples(0%-inhibition in the absence of inhibitor) and positive control samples(100%-inhibition) were assembled in replicates of four in each assayplate. The reactions were incubated at 25° C. and quenched by theaddition of 45 μL of termination buffer (100 mM HEPES, pH 7.5, 0.01%Triton X-100, 0.05% SDS).

The terminated assay plates were analyzed on LabChip® 3000 microfluidicelectrophoresis instrument (Perkin Elmer/Caliper Life Sciences). Thefluorescence intensity of the electrophoretically separatedde-acetylated product and substrate peptide was measured. Activity ineach sample was determined as the product to sum ratio (PSR): P/(S+P),where P is the peak height of the product peptide and S is the peakheight of the substrate peptide. Percent inhibition (P_(inh)) isdetermined using the following equation:

P_(inh)=(PSR_(0%)−PSR_(inh))/(PSR_(0%)−PSR_(100%))*100, where PSR_(inh)is the product sum ratio in the presence of inhibitor, PSR_(0%) is theaverage product sum ration in the absence of inhibitor, and PSR_(100%)is the average product sum ratio in 100%-inhibition control samples. TheIC₅₀ values of inhibitors were determined by fitting the %-inhibitioncurves with 4 parameter dose-response models using XLfit 4 software.

As set forth in Table 10, below, IC₅₀ values are defined as follows:IC50≤0.1 μM (+++); IC50>0.1 μM and ≤0.5 μM (++); IC50>0.5 μM (+).

TABLE 10 Inhibitory Concentration (IC₅₀) Values for RepresentativeCompounds against HDAC6. Activity COMPOUND NAME Range(S)-N-hydroxy-3-phenyl-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(R)-N-hydroxy-3-phenyl-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5- +tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-4-(oxetane-3-carbonyl)-3-phenyl-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(3S)-4-(8-oxabicyclo[3.2.1]octane-3-carbonyl)-N-hydroxy-3-phenyl-2,3,4,5-+++ tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-4-(4-fluorotetrahydro-2H-pyran-4-carbonyl)-N-hydroxy-3-phenyl-2,3,4,5-+++ tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-4-(cyclohexanecarbonyl)-N-hydroxy-3-phenyl-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-4-(cyclopentanecarbonyl)-N-hydroxy-3-phenyl-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-4-(cyclobutanecarbonyl)-N-hydroxy-3-phenyl-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-4-nicotinoyl-3-phenyl-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-4-isonicotinoyl-3-phenyl-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-4-(1-acetylpiperidine-4-carbonyl)-N-hydroxy-3-phenyl-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-3-phenyl-4-((S)-tetrahydro-2H-pyran-3-carbonyl)-2,3,4,5-+++ tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-3-phenyl-4-((R)-tetrahydro-2H-pyran-3-carbonyl)-2,3,4,5-+++ tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-3-phenyl-4-((S)-tetrahydrofuran-3-carbonyl)-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-3-phenyl-4-((R)-tetrahydrofuran-3-carbonyl)-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-4-((1s,4R)-4-methoxycyclohexane-1-carbonyl)-3-phenyl- +++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-4-((1r,4S)-4-methoxycyclohexane-1-carbonyl)-3-phenyl-2,3,4,5-+++ tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-4-(1-methylpiperidine-4-carbonyl)-3-phenyl-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-4-(1-methoxycyclopropane-1-carbonyl)-3-phenyl-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-4-(2-methoxy-2-methylpropanoyl)-3-phenyl-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-3-phenyl-4-pivaloyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-+++ 8-carboxamide (S)-N-hydroxy-3-phenyl-4-picolinoyl-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-4-isobutyryl-3-phenyl-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-4-(4-methyltetrahydro-2H-pyran-4-carbonyl)-3-phenyl-2,3,4,5-+++ tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-4-(1-methoxycyclohexane-1-carbonyl)-3-phenyl-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-3-(4- +++(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-3-(3-fluorophenyl)-N-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-+++ tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-3-(p-tolyl)-2,3,4,5-+++ tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-3-(4-chlorophenyl)-N-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-+++ tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-3-(3-chlorophenyl)-N-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-+++ tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-3-(4-fluorophenyl)-N-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-+++ tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-3-(o-tolyl)-2,3,4,5-+++ tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(R)-N-hydroxy-3-(pyridin-3-yl)-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-+++ tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-3-(pyridin-3-yl)-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-++ tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-3-(2-fluorophenyl)-N-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-+++ tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(R)-3-(2-fluorophenyl)-N-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-++ tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-3-(2- +++(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide (R)-N-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-3-(2- +(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide (S)-N-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-3-(3- +++(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide (R)-N-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-3-(3- ++(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-4-acetyl-N-hydroxy-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-+++ carboxamide (S)-4-(4-fluorobenzoyl)-N-hydroxy-3-phenyl-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-4-(1-(methoxymethyl)cyclopropane-1-carbonyl)-3-phenyl- +++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(3S)-N-hydroxy-3-phenyl-4-(tetrahydrofuran-2-carbonyl)-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

EQUIVALENTS

While the present disclosure has been described in conjunction with thespecific embodiments set forth above, many alternatives, modificationsand other variations thereof will be apparent to those of ordinary skillin the art. All such alternatives, modifications and variations areintended to fall within the spirit and scope of the present disclosure.

The invention claimed is:
 1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: X¹ is O; X² andX⁴ are each CR¹R²; X³ is CR^(1′)R^(2′); Y¹ and Y⁴ are not bonded to—C(O)NHOH and are each independently N or CR¹; Y² and Y³ are eachindependently N or CR¹ when not bonded to —C(O)NHOH, and Y² and Y³ are Cwhen bonded to —C(O)NHOH; wherein one of Y¹, Y², Y³, and Y⁴ is N; L isselected from the group consisting of —C(O)—, —C(O)(CR¹R²)_(m), and—C(O)(CR¹R²)_(m)O—, wherein L is bound to the ring nitrogen through thecarbonyl group; R is independently, and at each occurrence, selectedfrom the group consisting of —H, —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₄-C₈cycloalkenyl, —C₂-C₆ alkynyl, —C₃-C₈ cycloalkyl, —O₅—C₁₂ spirocyclyl,heterocyclyl, spiroheterocyclyl, aryl, and heteroaryl containing 1 to 5heteroatoms selected from the group consisting of N, S, P, and O,wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl,spirocyclyl, heterocyclyl, spiroheterocyclyl, aryl, or heteroaryl isoptionally substituted with one or more substituents selected from thegroup consisting of —OH, halogen, oxo, —NO₂, —CN, —R¹, —R², —OR³, —NHR³,—NR³R⁴, —S(O)₂NR³R⁴, —S(O)₂R¹, —C(O)R¹, —CO₂R¹, —NR³S(O)₂R¹, —S(O)R¹,—S(O)NR³R⁴, —NR³S(O)R¹, heterocyclyl, aryl, and heteroaryl containing 1to 5 heteroatoms selected from the group consisting of N, S, P, and O,with the proviso that R is not bound to L via a nitrogen atom; each R¹and R² are independently, at each occurrence, selected from the groupconsisting of —H, —R³, —R⁴, —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₄-C₈cycloalkenyl, —C₂-C₆ alkynyl, —C₃-C₈ cycloalkyl, heterocyclyl, aryl,heteroaryl containing 1 to 5 heteroatoms selected from the groupconsisting of N, S, P, and O, —OH, halogen, —NO₂, —CN, —NHC₁-C₆ alkyl,—N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)₂R⁵,—S(O)₂C₁-C₆ alkyl, —(C₁-C₆ alkyl)S(O)₂R⁵, —C(O)C₁-C₆ alkyl, —CO₂C₁-C₆alkyl, —N(C₁-C₆ alkyl)S(O)₂C₁-C₆ alkyl, and —(CHR⁵)_(n)NR³R⁴, whereineach alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl,aryl, or heteroaryl is optionally substituted with one or moresubstituents selected from the group consisting of —OH, halogen, —NO₂,oxo, —CN, —R⁵, —OR³, —NHR³, —NR³R⁴, —S(O)₂N(R³)₂, —S(O)₂R⁵, —C(O)R⁵,—CO₂R⁵, —NR³S(O)₂R⁵, —S(O)R⁵, —S(O)NR³R⁴, —NR³S(O)R⁵, heterocyclyl,aryl, and heteroaryl containing 1 to 5 heteroatoms selected from thegroup consisting of N, S, P, and O; each R^(1′) and R^(2′) areindependently selected from the group consisting of H, aryl, andheteroaryl containing 1 to 5 heteroatoms selected from the groupconsisting of N, S, P, and O, wherein each aryl or heteroaryl isoptionally substituted with one or more substituents selected from thegroup consisting of —OH, halogen, —NO₂, oxo, —CN, —R³, —R⁵, —OR³, —NHR³,—NR³R⁴, —S(O)₂N(R³)₂, —S(O)₂R⁵, —C(O)R⁵, —CO₂R⁵, —NR³S(O)₂R⁵, —S(O)R⁵,—S(O)NR³R⁴, —NR³S(O)R⁵, heterocyclyl, aryl, and heteroaryl containing 1to 5 heteroatoms selected from the group consisting of N, S, P, and O,wherein at least one of R^(1′) or R^(2′) is not H; R³ and R⁴ areindependently, at each occurrence, selected from the group consisting of—H, —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₄-C₈ cycloalkenyl, —C₂-C₆ alkynyl,—C₃-C₈ cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1 to 5heteroatoms selected from the group consisting of N, S, P, and O,—S(O)₂N(C₁-C₆ alkyl)₂, —S(O)₂C₁-C₆ alkyl, —(C₁-C₆ alkyl)S(O)₂R⁵,—C(O)C₁-C₆ alkyl, —CO₂C₁-C₆ alkyl, and —(CHR⁵)_(n)N(C₁-C₆ alkyl)₂,wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore substituents selected from the group consisting of —OH, halogen,—NO₂, oxo, —CN, —R⁵, —O(C₁-C₆ alkyl), —NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂,—S(O)₂N(C₁-C₆ alkyl)₂, —S(O)₂NH(C₁-C₆ alkyl), —C(O)C₁-C₆ alkyl,—CO₂C₁-C₆ alkyl, —N(C₁-C₆ alkyl)S(O)₂C₁-C₆ alkyl, —S(O)R⁵, —S(O)N(C₁-C₆alkyl)₂, —N(C₁-C₆ alkyl)S(O)R⁵, heterocyclyl, aryl, and heteroarylcontaining 1 to 5 heteroatoms selected from the group consisting of N,S, P, and O; R⁵ is independently, at each occurrence, selected from thegroup consisting of —H, —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₄-C₈cycloalkenyl, —C₂-C₆ alkynyl, —C₃-C₈ cycloalkyl, heterocyclyl, aryl,heteroaryl containing 1 to 5 heteroatoms selected from the groupconsisting of N, S, P, and O, —OH, halogen, —NO₂, —CN, —NHC₁-C₆ alkyl,—N(C₁-C₆ alkyl)₂, —S(O)₂NH(C₁-C₆ alkyl), —S(O)₂N(C₁-C₆ alkyl)₂,—S(O)₂C₁-C₆ alkyl, —C(O)C₁-C₆ alkyl, —CO₂C₁-C₆ alkyl, —N(C₁-C₆alkyl)SO₂C₁-C₆ alkyl, —S(O)(C₁-C₆ alkyl), —S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)(C₁-C₆ alkyl) and —(CH₂)_(n)N(C₁-C₆ alkyl)₂; each n isindependently and at each occurrence an integer from 0 to 6; and each mis independently and at each occurrence an integer from 1 to
 6. 2. Thecompound of claim 1, wherein the compound is of the Formula IA:

or a pharmaceutically acceptable salt thereof.
 3. The compound of claim2, wherein the compound is of the Formula IA-2:

or a pharmaceutically acceptable salt thereof.
 4. The compound of claim2, wherein the compound is of the Formula IA-3:

or a pharmaceutically acceptable salt thereof.
 5. The compound of claim2, wherein the compound is of the Formula IA-4:

or a pharmaceutically acceptable salt thereof.
 6. The compound of claim1, wherein the compound is of the Formula IB

or a pharmaceutically acceptable salt thereof.
 7. The compound of claim1, wherein one of and R² is optionally substituted aryl and the other ofand R^(2′) is H.
 8. The compound of claim 7, wherein L is —C(O)— and Ris an optionally substituted group selected from the group consisting of—C₁-C₆ alkyl, —C₃-C₈ cycloalkyl, heterocyclyl, aryl, and heteroaryl. 9.The compound of claim 8, wherein R is optionally substitutedheterocyclyl.
 10. The compound of claim 1, wherein one of R^(1′) andR^(2′) is optionally substituted heteroaryl and the other of and R² isH.
 11. The compound of claim 10, wherein L is —C(O)— and R is anoptionally substituted group selected from the group consisting of—C₁-C₆ alkyl, —C₃-C₈ cycloalkyl, heterocyclyl, aryl, and heteroaryl. 12.The compound of claim 11, wherein R is optionally substitutedheterocyclyl.
 13. A pharmaceutical composition comprising a compound ofclaim 1, and a pharmaceutically acceptable carrier.